6-31740370-T-C

Variant names:

• chr6-31740370-T-C
• rs409558
• NM_172166.4:c.-13-84T>C

Variant summary

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

The NM_172166.4(MSH5):​c.-13-84T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,421,498 control chromosomes in the GnomAD database, including 21,723 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 0.21 (3832 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17891 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• Publications: 35 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.271 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	NM_172166.4	MANE Select	c.-13-84T>C		intron	N/A	NP_751898.1
	MSH5	NM_172165.4		c.-13-84T>C		intron	N/A	NP_751897.1
	MSH5	NM_002441.5		c.-13-84T>C		intron	N/A	NP_002432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	ENST00000375750.9	TSL:1 MANE Select	c.-13-84T>C		intron	N/A	ENSP00000364903.3
	MSH5	ENST00000375703.7	TSL:1	c.-13-84T>C		intron	N/A	ENSP00000364855.3
	MSH5	ENST00000375755.8	TSL:1	c.-13-84T>C		intron	N/A	ENSP00000364908.3

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32387 AN: 152008 Hom.: 3815 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.158 AC: 200714 AN: 1269372 Hom.: 17891 Cov.: 19 AF XY: 0.157 AC XY: 98422 AN XY: 625352

African (AFR) AF: 0.266 AC: 7329 AN: 27540

American (AMR) AF: 0.280 AC: 7744 AN: 27672

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 4287 AN: 21150

East Asian (EAS) AF: 0.265 AC: 8864 AN: 33436

South Asian (SAS) AF: 0.167 AC: 11812 AN: 70638

European-Finnish (FIN) AF: 0.313 AC: 14831 AN: 47446

Middle Eastern (MID) AF: 0.183 AC: 749 AN: 4104

European-Non Finnish (NFE) AF: 0.138 AC: 136036 AN: 984442

Other (OTH) AF: 0.171 AC: 9062 AN: 52944

GnomAD4 genome AF: 0.213 AC: 32459 AN: 152126 Hom.: 3832 Cov.: 32 AF XY: 0.221 AC XY: 16403 AN XY: 74368

African (AFR) AF: 0.275 AC: 11420 AN: 41506

American (AMR) AF: 0.268 AC: 4106 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 691 AN: 3472

East Asian (EAS) AF: 0.174 AC: 898 AN: 5162

South Asian (SAS) AF: 0.175 AC: 847 AN: 4830

European-Finnish (FIN) AF: 0.329 AC: 3485 AN: 10580

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10362 AN: 67966

Other (OTH) AF: 0.214 AC: 453 AN: 2112

Alfa AF: 0.172 Hom.: 5144

Bravo AF: 0.213

Asia WGS AF: 0.229 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.51
PhyloP100		-0.029
PromoterAI		0.043	Neutral
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: rs409558; hg19: chr6-31708147; COSMIC: COSV65209852; COSMIC: COSV65209852;