NM_032793.5:c.93+16C>A

Variant names:

• chr1-39955401-C-A
• rs189000715
• NM_032793.5:c.93+16C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032793.5(MFSD2A):​c.93+16C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,510,868 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (19 hom.)
• Consequence: MFSD2A NM_032793.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0700
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-39955401-C-A is Benign according to our data. Variant chr1-39955401-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1598360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00162 (246/152280) while in subpopulation EAS AF = 0.0157 (81/5160). AF 95% confidence interval is 0.0129. There are 1 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

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+16C>A		intron	N/A	NP_116182.2
	MFSD2A	NM_001136493.3		c.93+16C>A		intron	N/A	NP_001129965.1	Q8NA29-1
	MFSD2A	NM_001349821.2		c.87+22C>A		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+16C>A		intron	N/A	ENSP00000361898.6	Q8NA29-2
	MFSD2A	ENST00000483824.5	TSL:1	n.228+16C>A		intron	N/A
	MFSD2A	ENST00000372809.5	TSL:2	c.93+16C>A		intron	N/A	ENSP00000361895.5	Q8NA29-1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00467 AC: 631 AN: 135100 AF XY: 0.00363

Gnomad AFR exome AF: 0.000107

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.000950

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00122 AC: 1664 AN: 1358588 Hom.: 19 Cov.: 30 AF XY: 0.00117 AC XY: 781 AN XY: 667010

African (AFR) AF: 0.0000666 AC: 2 AN: 30014

American (AMR) AF: 0.0159 AC: 479 AN: 30070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20460

East Asian (EAS) AF: 0.0225 AC: 808 AN: 35904

South Asian (SAS) AF: 0.00172 AC: 123 AN: 71344

European-Finnish (FIN) AF: 0.00139 AC: 67 AN: 48100

Middle Eastern (MID) AF: 0.000561 AC: 3 AN: 5352

European-Non Finnish (NFE) AF: 0.0000923 AC: 98 AN: 1061438

Other (OTH) AF: 0.00150 AC: 84 AN: 55906

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74436

African (AFR) AF: 0.000385 AC: 16 AN: 41576

American (AMR) AF: 0.00752 AC: 115 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0157 AC: 81 AN: 5160

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000503 Hom.: 1

Bravo AF: 0.00277

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly 15, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		0.070
PromoterAI		-0.057	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: rs189000715; hg19: chr1-40421073; COSMIC: COSV65686438; COSMIC: COSV65686438;