NM_005343.4:c.546G>A

Variant names:

• chr11-532660-C-T
• rs748639813
• NM_005343.4:c.546G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005343.4(HRAS):​c.546G>A​(p.Met182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M182V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.34
• Publications: 3 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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14834252).
• BP6: Variant 11-532660-C-T is Benign according to our data. Variant chr11-532660-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240138.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000959 (14/1460398) while in subpopulation AMR AF = 0.000179 (8/44720). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.546G>A	p.Met182Ile	missense	Exon 5 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.*115G>A		3_prime_UTR	Exon 6 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.546G>A	p.Met182Ile	missense	Exon 5 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.546G>A	p.Met182Ile	missense	Exon 5 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.*115G>A		3_prime_UTR	Exon 6 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.*115G>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248870 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460398 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726564

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111952

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Costello syndrome (2)
-	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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.49	N
PhyloP100		3.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.40		Loss of disorder (P = 0.0474)
MVP		0.59
MPC		1.1
ClinPred		0.045	T
GERP RS		2.1
Varity_R		0.088
gMVP		0.31
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748639813; hg19: chr11-532660; COSMIC: COSV54239695;