11-534197-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005343.4(HRAS):c.111+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,589,506 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 337 hom., cov: 33)

Exomes 𝑓: 0.055 ( 3120 hom. )

Consequence

HRAS
NM_005343.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.391

Publications

15 publications found

Variant links:

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

HRAS links:

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

LRRC56 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 39
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRRC56 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 11-534197-C-T is Benign according to our data. Variant chr11-534197-C-T is described in ClinVar as Benign. ClinVar VariationId is 40432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4 link	c.111+15G>A		intron_variant	Intron 2 of 5	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.111+15G>A		intron_variant	Intron 2 of 5	ENST00000417302.7	NP_789765.1	P01112-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8 link	c.111+15G>A		intron_variant	Intron 2 of 5	1	NM_005343.4	ENSP00000309845.7		P01112-1
HRAS	ENST00000417302.7 link	c.111+15G>A		intron_variant	Intron 2 of 5	5	NM_176795.5	ENSP00000388246.1		P01112-2

Frequencies

GnomAD3 genomes

AF:

0.0478

AC:

7270

AN:

152158

Hom.:

336

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.0424

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.0892

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0448

Gnomad OTH

AF:

0.0636

GnomAD2 exomes

AF:

0.0739

AC:

18380

AN:

248758

AF XY:

0.0709

show subpopulations

Gnomad AFR exome

AF:

0.00947

Gnomad AMR exome

AF:

0.193

Gnomad ASJ exome

AF:

0.0430

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0420

Gnomad OTH exome

AF:

0.0699

GnomAD4 exome

AF:

0.0546

AC:

78409

AN:

1437228

Hom.:

3120

Cov.:

AF XY:

0.0551

AC XY:

39480

AN XY:

716572

show subpopulations

African (AFR)

AF:

0.00851

AC:

281

AN:

33006

American (AMR)

AF:

0.188

AC:

8378

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.0411

AC:

1067

AN:

25980

East Asian (EAS)

AF:

0.147

AC:

5808

AN:

39568

South Asian (SAS)

AF:

0.0952

AC:

8168

AN:

85812

European-Finnish (FIN)

AF:

0.0240

AC:

1252

AN:

52086

Middle Eastern (MID)

AF:

0.0660

AC:

378

AN:

5730

European-Non Finnish (NFE)

AF:

0.0453

AC:

49380

AN:

1090898

Other (OTH)

AF:

0.0621

AC:

3697

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

4095

8190

12284

16379

20474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2096

4192

6288

8384

10480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0478

AC:

7274

AN:

152278

Hom.:

337

Cov.:

AF XY:

0.0500

AC XY:

3725

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0111

AC:

461

AN:

41552

American (AMR)

AF:

0.135

AC:

2060

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

147

AN:

3470

East Asian (EAS)

AF:

0.147

AC:

761

AN:

5176

South Asian (SAS)

AF:

0.0891

AC:

430

AN:

4826

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10626

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0448

AC:

3044

AN:

68016

Other (OTH)

AF:

0.0630

AC:

133

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

357

715

1072

1430

1787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0478

Hom.:

Bravo

AF:

0.0543

Asia WGS

AF:

0.100

AC:

348

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.111+15G>A in Intron 02 of HRAS: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 4.1% (291/7016) of European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS; dbSNP rs41258054). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 12, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HRAS c.111+15G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.074 in 248758 control chromosomes, predominantly at a frequency of 0.19 within the Latino subpopulation in the gnomAD database, including 688 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 80000-folds over the estimated maximal expected allele frequency for a pathogenic variant in HRAS causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 21, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Costello syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.5

(source)

DANN

Benign

0.82

PhyloP100

-0.39

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over