dbSNP rs12628: HRAS:p.His27His (chr11-534242-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005343.4(HRAS):c.81T>C(p.His27His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,612,572 control chromosomes in the GnomAD database, including 90,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.34 ( 9044 hom., cov: 33)

Exomes 𝑓: 0.33 ( 81035 hom. )

Consequence

HRAS
NM_005343.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:15O:1

Conservation

PhyloP100: 1.91

Publications

130 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: Ambry Genetics, ClinGen, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 11-534242-A-G is Benign according to our data. Variant chr11-534242-A-G is described in ClinVar as Benign. ClinVar VariationId is 40431.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=1.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HRAS	NM_005343.4	MANE Select	c.81T>C	p.His27His	synonymous	Exon 2 of 6	NP_005334.1	P01112-1
HRAS	NM_176795.5	MANE Plus Clinical	c.81T>C	p.His27His	synonymous	Exon 2 of 6	NP_789765.1	P01112-2
HRAS	NM_001130442.3		c.81T>C	p.His27His	synonymous	Exon 2 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HRAS	ENST00000311189.8	TSL:1 MANE Select	c.81T>C	p.His27His	synonymous	Exon 2 of 6	ENSP00000309845.7	P01112-1
HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.81T>C	p.His27His	synonymous	Exon 2 of 6	ENSP00000388246.1	P01112-2
HRAS	ENST00000493230.5	TSL:1	n.81T>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51764

AN:

151950

Hom.:

9032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.335

GnomAD2 exomes

AF:

0.316

AC:

79100

AN:

250438

AF XY:

0.311

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.381

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.339

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.330

AC:

482463

AN:

1460504

Hom.:

81035

Cov.:

AF XY:

0.328

AC XY:

238255

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.375

AC:

12539

AN:

33454

American (AMR)

AF:

0.376

AC:

16833

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

7074

AN:

26124

East Asian (EAS)

AF:

0.179

AC:

7114

AN:

39694

South Asian (SAS)

AF:

0.254

AC:

21876

AN:

86252

European-Finnish (FIN)

AF:

0.278

AC:

14723

AN:

53054

Middle Eastern (MID)

AF:

0.270

AC:

1558

AN:

5766

European-Non Finnish (NFE)

AF:

0.344

AC:

381912

AN:

1111100

Other (OTH)

AF:

0.312

AC:

18834

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

16685

33371

50056

66742

83427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12200

24400

36600

48800

61000

<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:

0.341

AC:

51809

AN:

152068

Hom.:

9044

Cov.:

AF XY:

0.336

AC XY:

25012

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.380

AC:

15758

AN:

41486

American (AMR)

AF:

0.373

AC:

5704

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

931

AN:

3470

East Asian (EAS)

AF:

0.187

AC:

968

AN:

5168

South Asian (SAS)

AF:

0.253

AC:

1216

AN:

4814

European-Finnish (FIN)

AF:

0.257

AC:

2721

AN:

10592

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.344

AC:

23398

AN:

67946

Other (OTH)

AF:

0.338

AC:

714

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1828

3656

5485

7313

9141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.341

Hom.:

7725

Bravo

AF:

0.348

Asia WGS

AF:

0.247

AC:

856

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Costello syndrome (3)

not provided (4)

RASopathy (2)

Cardiovascular phenotype (1)

Noonan syndrome and Noonan-related syndrome (1)

Squamous cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.7

(source)

DANN

Benign

0.82

PhyloP100

1.9

PromoterAI

-0.040

Neutral

(source)

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over