rs750686551

Variant names:

• chr1-39958645-A-G
• rs750686551
• NM_032793.5:c.229-56A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032793.5(MFSD2A):​c.229-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,888 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 (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MFSD2A NM_032793.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.117
• 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-39958645-A-G is Benign according to our data. Variant chr1-39958645-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2987673.Status of the report is criteria_provided_single_submitter, 1 stars.

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.229-56A>G		intron	N/A	NP_116182.2
	MFSD2A	NM_001136493.3		c.229-17A>G		intron	N/A	NP_001129965.1	Q8NA29-1
	MFSD2A	NM_001349821.2		c.223-56A>G		intron	N/A	NP_001336750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD2A	ENST00000372811.10	TSL:1 MANE Select	c.229-56A>G		intron	N/A	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.364-56A>G		intron	N/A
	MFSD2A	ENST00000372809.5	TSL:2	c.229-17A>G		intron	N/A	ENSP00000361895.5	Q8NA29-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251358 AF XY: 0.00000736

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111962

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

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	-0.85
CADD	Benign	3.9
DANN	Benign	0.70
PhyloP100		0.12
BranchPoint Hunter		0.0

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: rs750686551; hg19: chr1-40424317;