rs5743185

Variant names:

• chr2-189873112-G-A
• rs5743185
• NM_000534.5:c.2474-384G>A

Variant summary

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

The NM_000534.5(PMS1):​c.2474-384G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 152,220 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.060 (384 hom., cov: 32)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 13 publications found

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]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000300477 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. 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
	PMS1	NM_000534.5	MANE Select	c.2474-384G>A		intron	N/A	NP_000525.1
	PMS1	NM_001321045.2		c.2474-384G>A		intron	N/A	NP_001307974.1
	PMS1	NM_001321047.2		c.2474-384G>A		intron	N/A	NP_001307976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.2474-384G>A		intron	N/A	ENSP00000406490.3
	PMS1	ENST00000409593.5	TSL:1	c.1343-384G>A		intron	N/A	ENSP00000387169.1
	PMS1	ENST00000424059.1	TSL:1	n.1972-384G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9066 AN: 152102 Hom.: 384 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0641

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0596 AC: 9066 AN: 152220 Hom.: 384 Cov.: 32 AF XY: 0.0570 AC XY: 4243 AN XY: 74412

African (AFR) AF: 0.0175 AC: 728 AN: 41542

American (AMR) AF: 0.0543 AC: 830 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4816

European-Finnish (FIN) AF: 0.0479 AC: 506 AN: 10574

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0919 AC: 6248 AN: 68012

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0560 Hom.: 160

Bravo AF: 0.0580

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.45
DANN	Benign	0.84
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5743185; hg19: chr2-190737838;