rs727502800

Variant names:

• chr4-127921860-C-G
• rs727502800
• NM_001371596.2:c.1102G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 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. 3/3 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. D368N) has been classified as Likely pathogenic.

• 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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• macular dystrophy with central cone involvement

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-127921860-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3590142.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. 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 VariationId is 162380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371596.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	NM_001371596.2	MANE Select	c.1102G>C	p.Asp368His	missense splice_region	Exon 10 of 12	NP_001358525.1
	MFSD8	NM_001371591.2		c.1102G>C	p.Asp368His	missense splice_region	Exon 10 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.1108G>C	p.Asp370His	missense splice_region	Exon 10 of 12	NP_001358521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.1102G>C	p.Asp368His	missense splice_region	Exon 10 of 12	ENSP00000493218.2
	MFSD8	ENST00000296468.8	TSL:1	c.1102G>C	p.Asp368His	missense splice_region	Exon 11 of 13	ENSP00000296468.3
	MFSD8	ENST00000641186.1		c.988G>C	p.Asp330His	missense splice_region	Exon 9 of 11	ENSP00000493347.1

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

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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"). 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.

Jan 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 19, 2019

Tim Yu lab, Boston Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Macular dystrophy with central cone involvement Pathogenic:1

Jan 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.018	D
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.77		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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727502800; hg19: chr4-128843015;