4-127930752-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001371596.2(MFSD8):​c.929G>A​(p.Gly310Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G310A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.61
• Publications: 11 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: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 4-127930752-C-T is Pathogenic according to our data. 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	NM_001371596.2	MANE Select	c.929G>A	p.Gly310Asp	missense	Exon 9 of 12	NP_001358525.1	Q8NHS3-1
	MFSD8	NM_001371591.2		c.929G>A	p.Gly310Asp	missense	Exon 9 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.935G>A	p.Gly312Asp	missense	Exon 9 of 12	NP_001358521.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.929G>A	p.Gly310Asp	missense	Exon 9 of 12	ENSP00000493218.2	Q8NHS3-1
	MFSD8	ENST00000296468.8	TSL:1	c.929G>A	p.Gly310Asp	missense	Exon 10 of 13	ENSP00000296468.3	Q8NHS3-1
	MFSD8	ENST00000945724.1		c.917G>A	p.Gly306Asp	missense	Exon 9 of 12	ENSP00000615783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 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: 0.00000270 AC: 3 AN: 1111730

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronal ceroid lipofuscinosis 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.94		Gain of catalytic residue at G310 (P = 0.1127)
MVP		0.85
MPC		0.56
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.99
Mutation Taster		=4/96	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; COSMIC: COSV99614085; COSMIC: COSV99614085;