8-10054556-C-T

Variant names:

• chr8-10054556-C-T
• rs891281233
• NM_012331.5:c.40C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012331.5(MSRA):​c.40C>T​(p.Leu14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,587,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: MSRA NM_012331.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.463
• Publications: 2 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]

MSRA-DT (HGNC:55400): (MSRA divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040919036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5	c.40C>T	p.Leu14Phe	missense_variant	Exon 1 of 6	ENST00000317173.9	NP_036463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRA	ENST00000317173.9	c.40C>T	p.Leu14Phe	missense_variant	Exon 1 of 6	1	NM_012331.5	ENSP00000313921.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152036 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000133 AC: 3 AN: 226332 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000258 AC: 37 AN: 1435068 Hom.: 0 Cov.: 32 AF XY: 0.0000280 AC XY: 20 AN XY: 713888

African (AFR) AF: 0.00 AC: 0 AN: 30760

American (AMR) AF: 0.00 AC: 0 AN: 42032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 35958

South Asian (SAS) AF: 0.00 AC: 0 AN: 83968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000318 AC: 35 AN: 1099158

Other (OTH) AF: 0.0000337 AC: 2 AN: 59314

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152036 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40C>T (p.L14F) alteration is located in exon 1 (coding exon 1) of the MSRA gene. This alteration results from a C to T substitution at nucleotide position 40, causing the leucine (L) at amino acid position 14 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.5
DANN	Benign	0.89
DEOGEN2	Benign	0.19	T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		-0.46
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.21
MutPred		0.25		Loss of MoRF binding (P = 0.1152);Loss of MoRF binding (P = 0.1152);Loss of MoRF binding (P = 0.1152);
MVP		0.061
MPC		0.0016
ClinPred		0.058	T
GERP RS		-0.32
PromoterAI		-0.029	Neutral
Varity_R		0.11
gMVP		0.26
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs891281233; hg19: chr8-9912066; COSMIC: COSV100413784; COSMIC: COSV100413784;