rs727502800

chr4-127921860-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001371596.2(MFSD8):c.1102G>C(p.Asp368His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D368G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFSD8 NM_001371596.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.99

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-127921860-C-G is Pathogenic according to our data. Variant chr4-127921860-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 162380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127921860-C-G is described in Lovd as [Likely_pathogenic]. Variant chr4-127921860-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.1102G>C	p.Asp368His	missense_variant, splice_region_variant	10/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.1102G>C	p.Asp368His	missense_variant, splice_region_variant	10/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 11 and introduces a premature termination codon (PMID: 25227500). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 162380). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 17564970, 31597037). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 368 of the MFSD8 protein (p.Asp368His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Tim Yu lab, Boston Children's Hospital	Jul 19, 2019	The MFSD8 c.1102C>G variant was found in a patient with a clinical phenotype consistent with classical CLN7 Batten disease. This variant has been previously reported in patients with Batten disease. It results in a missense change (p.D368H) and has also been reported to cause skipping of exon 11 (Sintola et al, 2007; Roosing et al, 2015). It is absent from gnomAD. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -

Macular dystrophy with central cone involvement Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
Polyphen		0.99	D;D;.;.;.;.;.;.;.;.
Vest4		0.62
MutPred		0.77		Loss of glycosylation at S373 (P = 0.0462);Loss of glycosylation at S373 (P = 0.0462);.;.;.;.;.;.;.;Loss of glycosylation at S373 (P = 0.0462);
MVP		0.87
MPC		0.48
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.24
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727502800; hg19: chr4-128843015;