1-39955403-C-T

Variant names:

• chr1-39955403-C-T
• rs533659450
• NM_032793.5:c.93+18C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_032793.5(MFSD2A):​c.93+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000053 in 1,510,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MFSD2A NM_032793.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.122
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-39955403-C-T is Benign according to our data. Variant chr1-39955403-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3628218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000315 (48/152258) while in subpopulation AMR AF = 0.00268 (41/15298). AF 95% confidence interval is 0.00203. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.93+18C>T		intron	N/A	NP_116182.2
	MFSD2A	NM_001136493.3		c.93+18C>T		intron	N/A	NP_001129965.1	Q8NA29-1
	MFSD2A	NM_001349821.2		c.87+24C>T		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.93+18C>T		intron	N/A	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.228+18C>T		intron	N/A
	MFSD2A	ENST00000372809.5	TSL:2	c.93+18C>T		intron	N/A	ENSP00000361895.5	Q8NA29-1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0000299 AC: 4 AN: 133900 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000643

GnomAD4 exome AF: 0.0000236 AC: 32 AN: 1358034 Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 11 AN XY: 666758

African (AFR) AF: 0.0000333 AC: 1 AN: 29998

American (AMR) AF: 0.000367 AC: 11 AN: 29946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20502

East Asian (EAS) AF: 0.00 AC: 0 AN: 35874

South Asian (SAS) AF: 0.00 AC: 0 AN: 71412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 0.00000471 AC: 5 AN: 1061050

Other (OTH) AF: 0.000268 AC: 15 AN: 55906

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.00268 AC: 41 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-0.65
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		0.12
PromoterAI		-0.013	Neutral

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: rs533659450; hg19: chr1-40421075;