NM_172166.4:c.261T>G

Variant names:

• chr6-31741276-T-G
• rs777790620
• NM_172166.4:c.261T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_172166.4(MSH5):​c.261T>G​(p.Leu87Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: MSH5 NM_172166.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0380
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-31741276-T-G is Benign according to our data. Variant chr6-31741276-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3033693.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.038 with no splicing effect.

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.261T>G	p.Leu87Leu	synonymous	Exon 3 of 25	NP_751898.1	O43196-1
	MSH5	NM_172165.4		c.261T>G	p.Leu87Leu	synonymous	Exon 3 of 25	NP_751897.1	O43196-2
	MSH5	NM_002441.5		c.261T>G	p.Leu87Leu	synonymous	Exon 3 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.261T>G	p.Leu87Leu	synonymous	Exon 3 of 25	ENSP00000364903.3	O43196-1
	MSH5	ENST00000375703.7	TSL:1	c.261T>G	p.Leu87Leu	synonymous	Exon 3 of 25	ENSP00000364855.3	O43196-2
	MSH5	ENST00000375755.8	TSL:1	c.261T>G	p.Leu87Leu	synonymous	Exon 3 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 151012 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000568 AC: 14 AN: 246524 AF XY: 0.0000893

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1460320 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52264

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1111764

Other (OTH) AF: 0.0000331 AC: 2 AN: 60342

GnomAD4 genome AF: 0.0000464 AC: 7 AN: 151012 Hom.: 0 Cov.: 31 AF XY: 0.0000407 AC XY: 3 AN XY: 73656

African (AFR) AF: 0.0000244 AC: 1 AN: 41018

American (AMR) AF: 0.00 AC: 0 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67874

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MSH5-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.3
DANN	Benign	0.83
PhyloP100		0.038
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs777790620; hg19: chr6-31709053;