rs147084726

chr2-189854273-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

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. 16/21 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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005335659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.1001C>T	p.Thr334Met	missense_variant	9/13	ENST00000441310.7
LOC105373796	XR_001739151.2	n.319-1416G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.1001C>T	p.Thr334Met	missense_variant	9/13	1	NM_000534.5	P1

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

GnomAD3 exomes AF: 0.000753 AC: 179 AN: 237596 Hom.: 0 AF XY: 0.00105 AC XY: 135 AN XY: 128612

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 SAS exome AF: 0.00500

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

Gnomad4 AMR exome AF: 0.000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000554

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

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00541

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000765 Hom.: 0

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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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
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	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

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;