8-10054520-C-G

Position:

• chr8-10054520-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_012331.5(MSRA):​c.4C>G​(p.Leu2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: MSRA NM_012331.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 2 ACMG points.

• PM1: In a lipid_moiety_binding_region N-myristoyl glycine (size 0) in uniprot entity MSRA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20750797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSRA	NM_012331.5	c.4C>G	p.Leu2Val	missense_variant	1/6	ENST00000317173.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSRA	ENST00000317173.9	c.4C>G	p.Leu2Val	missense_variant	1/6	1	NM_012331.5	P1
	ENST00000659604.1	n.116+406G>C		intron_variant, non_coding_transcript_variant
MSRA	ENST00000518255.5	c.4C>G	p.Leu2Val	missense_variant	1/6	5
MSRA	ENST00000441698.6	c.4C>G	p.Leu2Val	missense_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Nov 09, 2023

The c.4C>G (p.L2V) alteration is located in exon 1 (coding exon 1) of the MSRA gene. This alteration results from a C to G substitution at nucleotide position 4, causing the leucine (L) at amino acid position 2 to be replaced by a valine (V). 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	0.086
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N;N;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.33
MutPred		0.18		Gain of MoRF binding (P = 0.0905);Gain of MoRF binding (P = 0.0905);Gain of MoRF binding (P = 0.0905);
MVP		0.17
MPC		0.0017
ClinPred		0.22	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.37

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: rs1369282579; hg19: chr8-9912030;