rs377029630

Variant names:

• chr4-127939959-C-T
• rs377029630
• NM_001371596.2:c.592G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001371596.2(MFSD8):​c.592G>A​(p.Val198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.604
• 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: 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19632572).

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.592G>A	p.Val198Met	missense	Exon 6 of 12	NP_001358525.1	Q8NHS3-1
	MFSD8	NM_001371591.2		c.592G>A	p.Val198Met	missense	Exon 6 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.598G>A	p.Val200Met	missense	Exon 6 of 12	NP_001358521.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.592G>A	p.Val198Met	missense	Exon 6 of 12	ENSP00000493218.2	Q8NHS3-1
	MFSD8	ENST00000296468.8	TSL:1	c.592G>A	p.Val198Met	missense	Exon 7 of 13	ENSP00000296468.3	Q8NHS3-1
	MFSD8	ENST00000945724.1		c.580G>A	p.Val194Met	missense	Exon 6 of 12	ENSP00000615783.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251168 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461230 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726916

African (AFR) AF: 0.000239 AC: 8 AN: 33458

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111712

Other (OTH) AF: 0.0000663 AC: 4 AN: 60364

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.000314 AC: 13 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Late-infantile neuronal ceroid lipofuscinosis (1)
-	1	-	Neuronal ceroid lipofuscinosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Benign	0.027
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.60
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.47
Sift	Benign	0.17	T
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.45
MVP		0.80
MPC		0.46
ClinPred		0.091	T
GERP RS		2.7
PromoterAI		-0.011	Neutral
Varity_R		0.054
gMVP		0.50
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs377029630; hg19: chr4-128861114;