rs17207454

Variant names:

• chr6-31740187-C-T
• rs17207454
• ENST00000375755.8:c.-47C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The ENST00000375755.8(MSH5):​c.-47C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 370,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: MSH5 ENST00000375755.8 5_prime_UTR
• Scores: Splicing: ADA: 0.00008007
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000684 (104/152130) while in subpopulation NFE AF = 0.00135 (92/67968). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.-14+125C>T		intron_variant	Intron 1 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.-14+125C>T		intron_variant	Intron 1 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.-14+125C>T		intron_variant	Intron 1 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00135

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00111 AC: 241 AN: 217984 Hom.: 0 Cov.: 3 AF XY: 0.00108 AC XY: 122 AN XY: 112704

African (AFR) AF: 0.000325 AC: 2 AN: 6154

American (AMR) AF: 0.00 AC: 0 AN: 7498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8058

East Asian (EAS) AF: 0.00 AC: 0 AN: 17462

South Asian (SAS) AF: 0.00 AC: 0 AN: 11888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1092

European-Non Finnish (NFE) AF: 0.00167 AC: 227 AN: 136072

Other (OTH) AF: 0.000856 AC: 12 AN: 14026

GnomAD4 genome AF: 0.000684 AC: 104 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74374

African (AFR) AF: 0.000265 AC: 11 AN: 41480

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000699

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.8
DANN	Benign	0.94
PhyloP100		0.028
PromoterAI		-0.014	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.040		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: rs17207454; hg19: chr6-31707964;