chr1-39957115-T-G

Variant names:

• chr1-39957115-T-G
• rs2124755855
• NM_032793.5:c.122T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032793.5(MFSD2A):​c.122T>G​(p.Leu41Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFSD2A NM_032793.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 15, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032793.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD2A	NM_032793.5	MANE Select	c.122T>G	p.Leu41Trp	missense	Exon 2 of 14	NP_116182.2
	MFSD2A	NM_001136493.3		c.122T>G	p.Leu41Trp	missense	Exon 2 of 14	NP_001129965.1	Q8NA29-1
	MFSD2A	NM_001349821.2		c.116T>G	p.Leu39Trp	missense	Exon 2 of 14	NP_001336750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD2A	ENST00000372811.10	TSL:1 MANE Select	c.122T>G	p.Leu41Trp	missense	Exon 2 of 14	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.257T>G		non_coding_transcript_exon	Exon 2 of 12
	MFSD2A	ENST00000372809.5	TSL:2	c.122T>G	p.Leu41Trp	missense	Exon 2 of 14	ENSP00000361895.5	Q8NA29-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.64		Gain of loop (P = 0.0166)
MVP		0.043
MPC		1.8
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.76
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs2124755855; hg19: chr1-40422787;