chr8-10207815-CTT-C

Variant names:

• chr8-10207815-CTT-C
• rs77793822
• NM_012331.5:c.143-6_143-5delTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_012331.5(MSRA):​c.143-6_143-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,280,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: MSRA NM_012331.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.07
• Publications: 0 publications found

Genes affected

MSRA (HGNC:7377): (methionine sulfoxide reductase A) This gene encodes a ubiquitous and highly conserved protein that carries out the enzymatic reduction of methionine sulfoxide to methionine. Human and animal studies have shown the highest levels of expression in kidney and nervous tissue. The protein functions in the repair of oxidatively damaged proteins to restore biological activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 8-10207815-CTT-C is Benign according to our data. Variant chr8-10207815-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3038398.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5	c.143-6_143-5delTT		splice_region_variant, intron_variant	Intron 1 of 5	ENST00000317173.9	NP_036463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRA	ENST00000317173.9	c.143-6_143-5delTT		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_012331.5	ENSP00000313921.4

Frequencies

GnomAD3 genomes AF: 0.0000276 AC: 4 AN: 144984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000504

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: 0.000223

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00490 AC: 490 AN: 100002 AF XY: 0.00503

Gnomad AFR exome AF: 0.00528

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00536

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00108 AC: 1224 AN: 1135894 Hom.: 0 AF XY: 0.00112 AC XY: 638 AN XY: 567274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00174 AC: 45 AN: 25846

American (AMR) AF: 0.00313 AC: 105 AN: 33566

Ashkenazi Jewish (ASJ) AF: 0.00162 AC: 34 AN: 21010

East Asian (EAS) AF: 0.000968 AC: 31 AN: 32040

South Asian (SAS) AF: 0.00228 AC: 153 AN: 67088

European-Finnish (FIN) AF: 0.00222 AC: 89 AN: 40056

Middle Eastern (MID) AF: 0.00120 AC: 5 AN: 4156

European-Non Finnish (NFE) AF: 0.000806 AC: 697 AN: 864822

Other (OTH) AF: 0.00137 AC: 65 AN: 47310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000276 AC: 4 AN: 144984 Hom.: 0 Cov.: 32 AF XY: 0.0000284 AC XY: 2 AN XY: 70448

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000504 AC: 2 AN: 39674

American (AMR) AF: 0.00 AC: 0 AN: 14500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 5006

South Asian (SAS) AF: 0.00 AC: 0 AN: 4606

European-Finnish (FIN) AF: 0.000223 AC: 2 AN: 8962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65690

Other (OTH) AF: 0.00 AC: 0 AN: 1976

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00428 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MSRA-related disorder Benign:1

May 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=99/1	polymorphism

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: rs77793822; hg19: chr8-10065325;