chr8-10054547-C-T

Position:

• chr8-10054547-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012331.5(MSRA):​c.31C>T​(p.Leu11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,433,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: MSRA NM_012331.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1485374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSRA	NM_012331.5	c.31C>T	p.Leu11Phe	missense_variant	1/6	ENST00000317173.9	NP_036463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSRA	ENST00000317173.9	c.31C>T	p.Leu11Phe	missense_variant	1/6	1	NM_012331.5	ENSP00000313921	P1
	ENST00000659604.1	n.116+379G>A		intron_variant, non_coding_transcript_variant
MSRA	ENST00000518255.5	c.31C>T	p.Leu11Phe	missense_variant	1/6	5		ENSP00000429461
MSRA	ENST00000441698.6	c.31C>T	p.Leu11Phe	missense_variant	1/5	2		ENSP00000410912

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000628 AC: 9 AN: 1433896 Hom.: 0 Cov.: 32 AF XY: 0.00000981 AC XY: 7 AN XY: 713320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000819

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.31C>T (p.L11F) 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 31, causing the leucine (L) at amino acid position 11 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	0.071
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.50	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.058
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.0010	B;B;.
Vest4		0.42
MutPred		0.29		Loss of MoRF binding (P = 0.1254);Loss of MoRF binding (P = 0.1254);Loss of MoRF binding (P = 0.1254);
MVP		0.11
MPC		0.0017
ClinPred		0.25	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.39

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: rs1585050285; hg19: chr8-9912057;