1-154966186-T-C

Variant names:

• chr1-154966186-T-C
• rs8191979
• NM_001130040.2:c.1228A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130040.2(SHC1):​c.1228A>G​(p.Met410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,614,014 control chromosomes in the GnomAD database, including 1,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.062 (477 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1283 hom.)
• Consequence: SHC1 NM_001130040.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• Publications: 28 publications found

Genes affected

SHC1 (HGNC:10840): (SHC adaptor protein 1) This gene encodes three main isoforms that differ in activities and subcellular location. While all three are adapter proteins in signal transduction pathways, the longest (p66Shc) may be involved in regulating life span and the effects of reactive oxygen species. The other two isoforms, p52Shc and p46Shc, link activated receptor tyrosine kinases to the Ras pathway by recruitment of the GRB2/SOS complex. p66Shc is not involved in Ras activation. Unlike the other two isoforms, p46Shc is targeted to the mitochondrial matrix. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013918281).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130040.2. 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
	SHC1	NM_001130040.2	MANE Select	c.1228A>G	p.Met410Val	missense	Exon 9 of 12	NP_001123512.1
	SHC1	NM_183001.5		c.1228A>G	p.Met410Val	missense	Exon 9 of 12	NP_892113.4
	SHC1	NM_003029.5		c.898A>G	p.Met300Val	missense	Exon 10 of 13	NP_003020.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC1	ENST00000448116.7	TSL:1 MANE Select	c.1228A>G	p.Met410Val	missense	Exon 9 of 12	ENSP00000401303.3
	SHC1	ENST00000368445.9	TSL:1	c.1228A>G	p.Met410Val	missense	Exon 9 of 12	ENSP00000357430.5
	SHC1	ENST00000368453.8	TSL:1	c.898A>G	p.Met300Val	missense	Exon 10 of 13	ENSP00000357438.4

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 9341 AN: 152084 Hom.: 468 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0415 AC: 10421 AN: 251316 AF XY: 0.0404

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.0244

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0361 AC: 52821 AN: 1461812 Hom.: 1283 Cov.: 33 AF XY: 0.0364 AC XY: 26472 AN XY: 727216

African (AFR) AF: 0.142 AC: 4767 AN: 33478

American (AMR) AF: 0.0260 AC: 1161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 972 AN: 26128

East Asian (EAS) AF: 0.00181 AC: 72 AN: 39698

South Asian (SAS) AF: 0.0563 AC: 4853 AN: 86256

European-Finnish (FIN) AF: 0.0225 AC: 1203 AN: 53416

Middle Eastern (MID) AF: 0.108 AC: 625 AN: 5768

European-Non Finnish (NFE) AF: 0.0331 AC: 36772 AN: 1111950

Other (OTH) AF: 0.0397 AC: 2396 AN: 60394

GnomAD4 genome AF: 0.0617 AC: 9390 AN: 152202 Hom.: 477 Cov.: 32 AF XY: 0.0599 AC XY: 4455 AN XY: 74430

African (AFR) AF: 0.137 AC: 5700 AN: 41498

American (AMR) AF: 0.0294 AC: 449 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5190

South Asian (SAS) AF: 0.0498 AC: 240 AN: 4820

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2443 AN: 67990

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0335 Hom.: 120

Bravo AF: 0.0640

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.135 AC: 597

ESP6500EA AF: 0.0350 AC: 301

ExAC AF: 0.0454 AC: 5512

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0376

EpiControl AF: 0.0370

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N
PhyloP100		0.27
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.052
Sift	Benign	0.62	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.36
ClinPred		0.0012	T
GERP RS		1.8
PromoterAI		-0.029	Neutral
Varity_R		0.080
gMVP		0.15
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs8191979; hg19: chr1-154938662; COSMIC: COSV63534825; COSMIC: COSV63534825;