rs755011754

chr4-127957595-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001371596.2(MFSD8):c.63-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,597,604 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MFSD8 NM_001371596.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0830

Genes affected

MFSD8 (HGNC:28486): (major facilitator superfamily domain containing 8) This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.63-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.63-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001371596.2	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000133 AC: 33 AN: 248584 Hom.: 0 AF XY: 0.000112 AC XY: 15 AN XY: 134470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 200 AN: 1445466 Hom.: 1 Cov.: 26 AF XY: 0.000129 AC XY: 93 AN XY: 720176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000587

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.0000837

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000136

EpiCase AF: 0.000492

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2023	See Variant Classification Assertion Criteria. -

Late-infantile neuronal ceroid lipofuscinosis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Neuronal ceroid lipofuscinosis 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs755011754; hg19: chr4-128878750;