2-190437063-G-C

Variant names:

• chr2-190437063-G-C
• rs1279845837
• NM_017694.4:c.1034G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017694.4(MFSD6):​c.1034G>C​(p.Gly345Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G345R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MFSD6 NM_017694.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

Genes affected

MFSD6 (HGNC:24711): (major facilitator superfamily domain containing 6) Predicted to enable MHC class I protein binding activity and MHC class I receptor activity. Predicted to be involved in antigen processing and presentation of exogenous peptide antigen via MHC class I. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

NEMP2 (HGNC:33700): (nuclear envelope integral membrane protein 2) Predicted to be located in nuclear inner membrane. Predicted to be integral component of membrane. Predicted to be active in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30995306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD6	NM_017694.4	c.1034G>C	p.Gly345Ala	missense_variant	Exon 3 of 8	ENST00000392328.6	NP_060164.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD6	ENST00000392328.6	c.1034G>C	p.Gly345Ala	missense_variant	Exon 3 of 8	2	NM_017694.4	ENSP00000376141.1
MFSD6	ENST00000281416.11	c.1034G>C	p.Gly345Ala	missense_variant	Exon 1 of 6	1		ENSP00000281416.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251476 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1034G>C (p.G345A) alteration is located in exon 3 (coding exon 1) of the MFSD6 gene. This alteration results from a G to C substitution at nucleotide position 1034, causing the glycine (G) at amino acid position 345 to be replaced by an alanine (A). 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	0.10
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.40
DEOGEN2	Benign	0.0027	T;T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	1.1	N;N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.12	B;B
Vest4		0.56
MutPred		0.63		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.69
MPC		0.45
ClinPred		0.26	T
GERP RS		6.1
Varity_R		0.13
gMVP		0.81

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: rs1279845837; hg19: chr2-191301789;