1-39955305-G-A

Position:

• chr1-39955305-G-A

Variant summary

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

The NM_032793.5(MFSD2A):​c.13G>A​(p.Glu5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000542 in 1,291,790 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: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: MFSD2A NM_032793.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

Genes affected

MFSD2A (HGNC:25897): (MFSD2 lysolipid transporter A, lysophospholipid) The protein encoded by this gene is a transmembrane protein and sodium-dependent lysophosphatidylcholine transporter. The encoded protein is involved in the establishment of the blood-brain barrier and is required for brain growth and function. Defects in this gene are a cause of a progressive microcephaly syndrome. [provided by RefSeq, Mar 2017]

MFSD2A (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=0.2565999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD2A	NM_032793.5	c.13G>A	p.Glu5Lys	missense_variant	1/14	ENST00000372811.10	NP_116182.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD2A	ENST00000372811.10	c.13G>A	p.Glu5Lys	missense_variant	1/14	1	NM_032793.5	ENSP00000361898.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000542 AC: 7 AN: 1291790 Hom.: 0 Cov.: 30 AF XY: 0.00000635 AC XY: 4 AN XY: 629638

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: 0.00000680

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000880 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.13G>A (p.E5K) alteration is located in exon 1 (coding exon 1) of the MFSD2A gene. This alteration results from a G to A substitution at nucleotide position 13, causing the glutamic acid (E) at amino acid position 5 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.97	D;.;P
Vest4		0.41
MutPred		0.16		Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);
MVP		0.043
MPC		0.56
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.62
gMVP		0.52

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: rs748299994; hg19: chr1-40420977;