chr1-39955331-G-A

Variant names:

• chr1-39955331-G-A
• rs752299974
• NM_032793.5:c.39G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_032793.5(MFSD2A):​c.39G>A​(p.Ala13Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000921 in 1,443,634 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MFSD2A NM_032793.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.544
• 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-39955331-G-A is Benign according to our data. Variant chr1-39955331-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 726965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.544 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000999 (129/1291374) while in subpopulation MID AF = 0.000205 (1/4880). AF 95% confidence interval is 0.0000986. There are 0 homozygotes in GnomAdExome4. There are 68 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.39G>A	p.Ala13Ala	synonymous	Exon 1 of 14	NP_116182.2
	MFSD2A	NM_001136493.3		c.39G>A	p.Ala13Ala	synonymous	Exon 1 of 14	NP_001129965.1	Q8NA29-1
	MFSD2A	NM_001349821.2		c.39G>A	p.Ala13Ala	synonymous	Exon 1 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.39G>A	p.Ala13Ala	synonymous	Exon 1 of 14	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.174G>A		non_coding_transcript_exon	Exon 1 of 12
	MFSD2A	ENST00000372809.5	TSL:2	c.39G>A	p.Ala13Ala	synonymous	Exon 1 of 14	ENSP00000361895.5	Q8NA29-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000863 AC: 10 AN: 115914 AF XY: 0.0000793

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 129 AN: 1291374 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 68 AN XY: 629522

African (AFR) AF: 0.00 AC: 0 AN: 26908

American (AMR) AF: 0.00 AC: 0 AN: 21830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17860

East Asian (EAS) AF: 0.00 AC: 0 AN: 32492

South Asian (SAS) AF: 0.0000166 AC: 1 AN: 60348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46504

Middle Eastern (MID) AF: 0.000205 AC: 1 AN: 4880

European-Non Finnish (NFE) AF: 0.000116 AC: 119 AN: 1028022

Other (OTH) AF: 0.000152 AC: 8 AN: 52530

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		-0.54
PromoterAI		0.0034	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752299974; hg19: chr1-40421003;