rs409558

Positions:

• chr6-31740370-T-C

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH5	NM_172166.4	c.-13-84T>C		intron_variant		ENST00000375750.9	NP_751898.1
MSH5-SAPCD1	NR_037846.1	n.116-84T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.-13-84T>C		intron_variant		1	NM_172166.4	ENSP00000364903	A2

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

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.171

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

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.214

Alfa AF: 0.158 Hom.: 2339

Bravo AF: 0.213

Asia WGS AF: 0.229 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs409558; hg19: chr6-31708147; COSMIC: COSV65209852; COSMIC: COSV65209852;