rs1802127

Variant names:

• chr6-31762148-C-T
• rs1802127
• NM_172166.4:c.2356C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_172166.4(MSH5):​c.2356C>T​(p.Pro786Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,030 control chromosomes in the GnomAD database, including 1,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.049 (341 hom., cov: 32)
  • Exomes 𝑓: 0.021 (757 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.02
• Publications: 23 publications found

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015169978).
• BP6: Variant 6-31762148-C-T is Benign according to our data. Variant chr6-31762148-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056743.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	NM_172166.4	MANE Select	c.2356C>T	p.Pro786Ser	missense	Exon 24 of 25	NP_751898.1	O43196-1
	MSH5	NM_172165.4		c.2359C>T	p.Pro787Ser	missense	Exon 24 of 25	NP_751897.1	O43196-2
	MSH5	NM_002441.5		c.2356C>T	p.Pro786Ser	missense	Exon 24 of 25	NP_002432.1	A0A024RCM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	ENST00000375750.9	TSL:1 MANE Select	c.2356C>T	p.Pro786Ser	missense	Exon 24 of 25	ENSP00000364903.3	O43196-1
	MSH5	ENST00000375703.7	TSL:1	c.2359C>T	p.Pro787Ser	missense	Exon 24 of 25	ENSP00000364855.3	O43196-2
	MSH5	ENST00000375755.8	TSL:1	c.2356C>T	p.Pro786Ser	missense	Exon 24 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes AF: 0.0491 AC: 7470 AN: 152104 Hom.: 341 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0546

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0298 AC: 7502 AN: 251442 AF XY: 0.0256

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0206 AC: 30176 AN: 1461808 Hom.: 757 Cov.: 32 AF XY: 0.0199 AC XY: 14450 AN XY: 727204

African (AFR) AF: 0.116 AC: 3890 AN: 33474

American (AMR) AF: 0.0537 AC: 2400 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2819 AN: 26122

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39700

South Asian (SAS) AF: 0.00468 AC: 404 AN: 86252

European-Finnish (FIN) AF: 0.00217 AC: 116 AN: 53416

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5766

European-Non Finnish (NFE) AF: 0.0165 AC: 18306 AN: 1111972

Other (OTH) AF: 0.0322 AC: 1943 AN: 60394

GnomAD4 genome AF: 0.0492 AC: 7485 AN: 152222 Hom.: 341 Cov.: 32 AF XY: 0.0468 AC XY: 3483 AN XY: 74428

African (AFR) AF: 0.115 AC: 4758 AN: 41500

American (AMR) AF: 0.0546 AC: 834 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3470

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0191 AC: 1299 AN: 68020

Other (OTH) AF: 0.0696 AC: 147 AN: 2112

Alfa AF: 0.0320 Hom.: 645

Bravo AF: 0.0573

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.116 AC: 510

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0289 AC: 3508

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0260

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MSH5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.0
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.16
Sift	Benign	0.19	T
Sift4G	Benign	0.57	T
Polyphen		0.31	B
Vest4		0.099
MPC		0.59
ClinPred		0.0073	T
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.34
Mutation Taster		=98/2	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: rs1802127; hg19: chr6-31729925;