6-159907370-T-C

Variant names:

• chr6-159907370-T-C
• rs1201188264
• NM_002377.4:c.415T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002377.4(MAS1):​c.415T>C​(p.Trp139Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAS1 NM_002377.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

Genes affected

MAS1 (HGNC:6899): (MAS1 proto-oncogene, G protein-coupled receptor) This gene encodes a class I seven-transmembrane G-protein-coupled receptor. The encoded protein is a receptor for angiotensin-(1-7) and preferentially couples to the Gq protein, activating the phospholipase C signaling pathway. The encoded protein may play a role in multiple processes including hypotension, smooth muscle relaxation and cardioprotection by mediating the effects of angiotensin-(1-7). [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAS1	NM_002377.4	c.415T>C	p.Trp139Arg	missense_variant	Exon 3 of 3	ENST00000674077.2	NP_002368.1
MAS1	NM_001366704.2	c.415T>C	p.Trp139Arg	missense_variant	Exon 2 of 2		NP_001353633.1
MAS1	XM_047418776.1	c.415T>C	p.Trp139Arg	missense_variant	Exon 4 of 4		XP_047274732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAS1	ENST00000674077.2	c.415T>C	p.Trp139Arg	missense_variant	Exon 3 of 3		NM_002377.4	ENSP00000501180.2
MAS1	ENST00000252660.5	c.415T>C	p.Trp139Arg	missense_variant	Exon 1 of 1	6		ENSP00000252660.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251176 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415T>C (p.W139R) alteration is located in exon 1 (coding exon 1) of the MAS1 gene. This alteration results from a T to C substitution at nucleotide position 415, causing the tryptophan (W) at amino acid position 139 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.036	D
Polyphen		0.76	P
Vest4		0.81
MutPred		0.85		Gain of methylation at W139 (P = 0.0283);
MVP		0.83
MPC		0.64
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs1201188264; hg19: chr6-160328402;