chr4-127930752-C-G

Variant names:

• chr4-127930752-C-G
• rs118203975
• NM_001371596.2:c.929G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001371596.2(MFSD8):​c.929G>C​(p.Gly310Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G310D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-127930752-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1001.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.929G>C	p.Gly310Ala	missense_variant	Exon 9 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.929G>C	p.Gly310Ala	missense_variant	Exon 9 of 12		NM_001371596.2	ENSP00000493218.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461312 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111730

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with alanine at codon 310 of the MFSD8 protein (p.Gly310Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Benign	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.2	.;D;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.082	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98
MutPred		0.83		Loss of stability (P = 0.0485);Loss of stability (P = 0.0485);.;.;.;.;.;.;Loss of stability (P = 0.0485);.;.;.;Loss of stability (P = 0.0485);.;
MVP		0.77
MPC		0.50
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.95
Mutation Taster		=19/81	disease causing

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: rs118203975; hg19: chr4-128851907;