rs587778610

chr2-189818173-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000534.5(PMS1):c.575A>G(p.His192Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,622 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 not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.575A>G	p.His192Arg	missense_variant	5/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.575A>G	p.His192Arg	missense_variant	5/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426622 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 711786

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T;T;T;.;T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;D;D;D;D;D;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
Polyphen		1.0, 0.99, 0.99	.;.;.;D;D;D;.;.;.;.;.
Vest4		0.88, 0.88, 0.85, 0.81, 0.80, 0.84, 0.86
MutPred		0.52		Gain of MoRF binding (P = 0.0234);.;.;Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);.;.;
MVP		0.98
MPC		0.41
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.77
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778610; hg19: chr2-190682899;