chr4-127932985-G-A

Position:

chr4-127932985-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001371596.2(MFSD8):c.863C>T(p.Thr288Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,456,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 missense, splice_region

Scores

Splicing: ADA: 0.9883

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.65

Variant links:

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]

MFSD8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2 linkuse as main transcript	c.863C>T	p.Thr288Ile	missense_variant, splice_region_variant	8/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2 linkuse as main transcript	c.863C>T	p.Thr288Ile	missense_variant, splice_region_variant	8/12		NM_001371596.2	P1	Q8NHS3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251104

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135680

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1456300

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2022

Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Late-infantile neuronal ceroid lipofuscinosis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 18, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2013

p.Thr288Ile (ACC>ATC): c.863 C>T in exon 9 of the MFSD8 gene (NM_152778.2)The Thr288Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Thr288Ile in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Threonine residue is replaced by a non-polar Isoleucine residue. Thr288Ile alters a conserved position in the extracellular loop between the seventh and eighth transmembrane domains of the protein and another missense mutation (Thr294Lys) in this region has been reported in association with late-infantile neuronal ceroid lipofuscinoses (vLINCL) (Kousi et al., 2009; Aiello et al., 2009). In addition, multiple in-silico algorithms predict Thr288Ile is damaging to the structure/function of the protein. Based on the currently available information, it is unclear whether Thr288Ile is a disease-causing mutation or a rare benign variant.The variant is found in CHILD-EPI panel(s). -

Neuronal ceroid lipofuscinosis 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 288 of the MFSD8 protein (p.Thr288Ile). This variant is present in population databases (rs755384900, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 206156). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;T;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;.;D;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.078

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

M;M;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.7

.;D;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;D;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.95

MutPred

0.65

Loss of glycosylation at T291 (P = 0.0453);Loss of glycosylation at T291 (P = 0.0453);.;.;.;.;.;.;Loss of glycosylation at T291 (P = 0.0453);.;.;.;Loss of glycosylation at T291 (P = 0.0453);.;

MVP

0.80

MPC

0.51

ClinPred

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.70

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over