1-39955328-G-T

Variant names:

• chr1-39955328-G-T
• rs1219555623
• NM_032793.5:c.36G>T

Variant summary

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

The NM_001349823.2(MFSD2A):​c.-306G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,443,866 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: MFSD2A NM_001349823.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.161
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-39955328-G-T is Benign according to our data. Variant chr1-39955328-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2170357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000197 (3/152180) while in subpopulation EAS AF = 0.00058 (3/5170). AF 95% confidence interval is 0.000157. There are 0 homozygotes in GnomAd4. There are 3 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_001349823.2. 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.36G>T	p.Ala12Ala	synonymous	Exon 1 of 14	NP_116182.2
	MFSD2A	NM_001349823.2		c.-306G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001336752.1
	MFSD2A	NM_001287808.2		c.-173G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001274737.1	E7EPI8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD2A	ENST00000372811.10	TSL:1 MANE Select	c.36G>T	p.Ala12Ala	synonymous	Exon 1 of 14	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.171G>T		non_coding_transcript_exon	Exon 1 of 12
	MFSD2A	ENST00000420632.6	TSL:2	c.-173G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000391261.2	E7EPI8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000860 AC: 1 AN: 116282 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000232 AC: 3 AN: 1291686 Hom.: 0 Cov.: 30 AF XY: 0.00000159 AC XY: 1 AN XY: 629602

African (AFR) AF: 0.00 AC: 0 AN: 26912

American (AMR) AF: 0.00 AC: 0 AN: 21862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17878

East Asian (EAS) AF: 0.0000922 AC: 3 AN: 32532

South Asian (SAS) AF: 0.00 AC: 0 AN: 60402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4866

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1028270

Other (OTH) AF: 0.00 AC: 0 AN: 52500

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	-0.48
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-0.16
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1219555623; hg19: chr1-40421000;