6-24412345-T-C

Position:

• chr6-24412345-T-C

Variant summary

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

The NM_020662.4(MRS2):​c.538T>C​(p.Tyr180His) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,443,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MRS2 NM_020662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

MRS2 (HGNC:13785): (magnesium transporter MRS2) Enables magnesium ion transmembrane transporter activity. Involved in mitochondrial magnesium ion transmembrane transport. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16136247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRS2	NM_020662.4	c.538T>C	p.Tyr180His	missense_variant	5/11	ENST00000378386.8	NP_065713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRS2	ENST00000378386.8	c.538T>C	p.Tyr180His	missense_variant	5/11	1	NM_020662.4	ENSP00000367637	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1443070 Hom.: 0 Cov.: 31 AF XY: 0.00000975 AC XY: 7 AN XY: 717660

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: 0.0000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

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

Jun 13, 2024

The c.538T>C (p.Y180H) alteration is located in exon 5 (coding exon 5) of the MRS2 gene. This alteration results from a T to C substitution at nucleotide position 538, causing the tyrosine (Y) at amino acid position 180 to be replaced by a histidine (H). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	.;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0068
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.18	N;.;N;N
REVEL	Benign	0.059
Sift	Benign	0.43	T;.;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.034	.;.;B;B
Vest4		0.34
MutPred		0.54		.;.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);
MVP		0.45
MPC		0.54
ClinPred		0.76	D
GERP RS		4.3
Varity_R		0.081
gMVP		0.38

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: rs201401855; hg19: chr6-24412573;