chr1-39955047-C-A

Variant names:

• chr1-39955047-C-A
• rs3738668
• NM_032793.5:c.-246C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032793.5(MFSD2A):​c.-246C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 370,050 control chromosomes in the GnomAD database, including 3,997 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1134 hom., cov: 31)
  • Exomes 𝑓: 0.068 (2863 hom.)
• Consequence: MFSD2A NM_032793.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.132
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-39955047-C-A is Benign according to our data. Variant chr1-39955047-C-A is described in ClinVar as Benign. ClinVar VariationId is 1223952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD2A	NM_032793.5	c.-246C>A		upstream_gene_variant		ENST00000372811.10	NP_116182.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD2A	ENST00000372811.10	c.-246C>A		upstream_gene_variant		1	NM_032793.5	ENSP00000361898.6

Frequencies

GnomAD3 genomes AF: 0.0790 AC: 11942 AN: 151172 Hom.: 1128 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.0746

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.0749

GnomAD4 exome AF: 0.0681 AC: 14891 AN: 218760 Hom.: 2863 AF XY: 0.0649 AC XY: 7193 AN XY: 110810

African (AFR) AF: 0.162 AC: 1049 AN: 6484

American (AMR) AF: 0.132 AC: 839 AN: 6362

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 96 AN: 8428

East Asian (EAS) AF: 0.499 AC: 10297 AN: 20654

South Asian (SAS) AF: 0.0697 AC: 150 AN: 2152

European-Finnish (FIN) AF: 0.0389 AC: 712 AN: 18298

Middle Eastern (MID) AF: 0.0189 AC: 22 AN: 1164

European-Non Finnish (NFE) AF: 0.00520 AC: 731 AN: 140554

Other (OTH) AF: 0.0679 AC: 995 AN: 14664

GnomAD4 genome AF: 0.0791 AC: 11968 AN: 151290 Hom.: 1134 Cov.: 31 AF XY: 0.0833 AC XY: 6154 AN XY: 73880

African (AFR) AF: 0.160 AC: 6601 AN: 41182

American (AMR) AF: 0.122 AC: 1850 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3462

East Asian (EAS) AF: 0.443 AC: 2221 AN: 5018

South Asian (SAS) AF: 0.0740 AC: 352 AN: 4754

European-Finnish (FIN) AF: 0.0390 AC: 411 AN: 10528

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00488 AC: 331 AN: 67840

Other (OTH) AF: 0.0750 AC: 157 AN: 2092

Alfa AF: 0.0443 Hom.: 79

Bravo AF: 0.0914

Asia WGS AF: 0.272 AC: 944 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		-0.13
PromoterAI		-0.099	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3738668; hg19: chr1-40420719;