rs147084726

Variant names:

• chr2-189854273-C-T
• rs147084726
• NM_000534.5:c.1001C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000534.5(PMS1):​c.1001C>T​(p.Thr334Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,593,580 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.228

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

LOC105373796 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005335659).
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.1001C>T	p.Thr334Met	missense_variant	Exon 9 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.1001C>T	p.Thr334Met	missense_variant	Exon 9 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152018 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000753 AC: 179 AN: 237596 AF XY: 0.00105

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.000520

GnomAD4 exome AF: 0.000456 AC: 657 AN: 1441444 Hom.: 4 Cov.: 30 AF XY: 0.000612 AC XY: 438 AN XY: 715756

Gnomad4 AFR exome AF: 0.0000304 AC: 1 AN: 32854

Gnomad4 AMR exome AF: 0.000236 AC: 10 AN: 42354

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25588

Gnomad4 EAS exome AF: 0.0000508 AC: 2 AN: 39364

Gnomad4 SAS exome AF: 0.00515 AC: 413 AN: 80122

Gnomad4 FIN exome AF: 0.0000189 AC: 1 AN: 52878

Gnomad4 NFE exome AF: 0.000169 AC: 186 AN: 1103086

Gnomad4 Remaining exome AF: 0.000554 AC: 33 AN: 59582

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152136 Hom.: 1 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74372

Gnomad4 AFR AF: 0.0000723 AC: 0.0000722578 AN: 0.0000722578

Gnomad4 AMR AF: 0.000458 AC: 0.000458355 AN: 0.000458355

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00541 AC: 0.00540765 AN: 0.00540765

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.000161784 AN: 0.000161784

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000804 Hom.: 1

Bravo AF: 0.000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000942 AC: 114

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.81	T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.76	.;.;.;.;N;.;N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.59	.;.;N;.;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.18	.;.;T;.;T;T;T;T;T
Sift4G	Benign	0.20	.;T;T;T;T;T;T;T;T
Polyphen		0.64, 0.46	.;.;.;P;P;.;.;.;.
Vest4		0.096, 0.14, 0.090, 0.15, 0.091
MVP		0.88
MPC		0.079
ClinPred		0.011	T
GERP RS		0.90
Varity_R		0.014
gMVP		0.22
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147084726; hg19: chr2-190718999; COSMIC: COSV59719125; COSMIC: COSV59719125;