rs111352454

Variant names:

• chr11-533546-G-A
• rs111352454
• NM_005343.4:c.357C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-533546-G-A
• chr11-533546-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005343.4(HRAS):​c.357C>T​(p.Asp119Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.00197 in 1,613,866 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: HRAS NM_005343.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 4.12
• Publications: 2 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-533546-G-A is Benign according to our data. Variant chr11-533546-G-A is described in ClinVar as Benign. ClinVar VariationId is 40441.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00121 (184/152320) while in subpopulation AMR AF = 0.00222 (34/15300). AF 95% confidence interval is 0.00163. There are 3 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 184 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.357C>T	p.Asp119Asp	synonymous	Exon 4 of 6	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.357C>T	p.Asp119Asp	synonymous	Exon 4 of 6	NP_789765.1
	HRAS	NM_001318054.2		c.38C>T	p.Thr13Ile	missense	Exon 4 of 7	NP_001304983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.357C>T	p.Asp119Asp	synonymous	Exon 4 of 6	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.357C>T	p.Asp119Asp	synonymous	Exon 4 of 6	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.357C>T		non_coding_transcript_exon	Exon 4 of 7	ENSP00000434023.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00105 AC: 263 AN: 251364 AF XY: 0.00107

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00205 AC: 2995 AN: 1461546 Hom.: 5 Cov.: 35 AF XY: 0.00206 AC XY: 1501 AN XY: 727092

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00245 AC: 2728 AN: 1111974

Other (OTH) AF: 0.00290 AC: 175 AN: 60388

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74488

African (AFR) AF: 0.000409 AC: 17 AN: 41570

American (AMR) AF: 0.00222 AC: 34 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00120

EpiCase AF: 0.00256

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Costello syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	HRAS-related disorder (1)
-	-	1	Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.4
DANN	Benign	0.93
PhyloP100		4.1
PromoterAI		-0.016	Neutral
Mutation Taster		=68/32	polymorphism

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: rs111352454; hg19: chr11-533546; COSMIC: COSV54243286; COSMIC: COSV54243286;