chr11-534197-C-T

Variant names:

• chr11-534197-C-T
• rs41258054
• NM_005343.4:c.111+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). The gene HRAS is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.048 (337 hom., cov: 33)
  • Exomes 𝑓: 0.055 (3120 hom.)
• Consequence: HRAS NM_005343.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.391
• Publications: 16 publications found

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]

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

ACMG classification

Specifications for HRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.111+15G>A		intron	N/A	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.111+15G>A		intron	N/A	NP_789765.1	P01112-2
	LRRC56	NM_001441284.1		c.-161-5383C>T		intron	N/A	NP_001428213.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.111+15G>A		intron	N/A	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.111+15G>A		intron	N/A	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.111+15G>A		intron	N/A	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 7270 AN: 152158 Hom.: 336 Cov.: 33

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

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.: 28 AF XY: 0.0551 AC XY: 39480 AN XY: 716572

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

GnomAD4 genome AF: 0.0478 AC: 7274 AN: 152278 Hom.: 337 Cov.: 33 AF XY: 0.0500 AC XY: 3725 AN XY: 74454

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: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3044 AN: 68016

Other (OTH) AF: 0.0630 AC: 133 AN: 2112

Alfa AF: 0.0478 Hom.: 42

Bravo AF: 0.0543

Asia WGS AF: 0.100 AC: 348 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Costello syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.82
PhyloP100		-0.39
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41258054; hg19: chr11-534197; COSMIC: COSV54242364; COSMIC: COSV54242364;