rs707915

Variant names:

• chr6-31743191-T-A
• rs707915
• NM_172166.4:c.415+21T>A

Variant summary

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

The NM_172166.4(MSH5):​c.415+21T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,610,994 control chromosomes in the GnomAD database, including 5,250 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 0.11 (1204 hom., cov: 31)
  • Exomes 𝑓: 0.067 (4046 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• Publications: 44 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.415+21T>A		intron_variant	Intron 5 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.415+21T>A		intron_variant	Intron 5 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.415+21T>A		intron_variant	Intron 5 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16386 AN: 151998 Hom.: 1205 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0684

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0799 AC: 19697 AN: 246490 AF XY: 0.0798

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.0937

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0732

GnomAD4 exome AF: 0.0674 AC: 98278 AN: 1458878 Hom.: 4046 Cov.: 30 AF XY: 0.0679 AC XY: 49321 AN XY: 725870

African (AFR) AF: 0.215 AC: 7190 AN: 33420

American (AMR) AF: 0.0561 AC: 2510 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 1428 AN: 26122

East Asian (EAS) AF: 0.0450 AC: 1785 AN: 39688

South Asian (SAS) AF: 0.105 AC: 9017 AN: 86200

European-Finnish (FIN) AF: 0.0671 AC: 3513 AN: 52346

Middle Eastern (MID) AF: 0.0774 AC: 446 AN: 5760

European-Non Finnish (NFE) AF: 0.0614 AC: 68148 AN: 1110322

Other (OTH) AF: 0.0703 AC: 4241 AN: 60306

GnomAD4 genome AF: 0.108 AC: 16387 AN: 152116 Hom.: 1204 Cov.: 31 AF XY: 0.107 AC XY: 7971 AN XY: 74366

African (AFR) AF: 0.204 AC: 8442 AN: 41470

American (AMR) AF: 0.0698 AC: 1065 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.0752 AC: 389 AN: 5176

South Asian (SAS) AF: 0.116 AC: 560 AN: 4820

European-Finnish (FIN) AF: 0.0684 AC: 725 AN: 10602

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4723 AN: 68000

Other (OTH) AF: 0.106 AC: 224 AN: 2108

Alfa AF: 0.0750 Hom.: 308

Bravo AF: 0.113

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs707915; hg19: chr6-31710968;