rs76506918

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001371596.2(MFSD8):c.961G>A(p.Val321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V321V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.776

Publications

2 publications found

Variant links:

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)

MFSD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13317865).

BP6

Variant 4-127930720-C-T is Benign according to our data. Variant chr4-127930720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533369.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MFSD8	NM_001371596.2	MANE Select	c.961G>A	p.Val321Ile	missense	Exon 9 of 12	NP_001358525.1	Q8NHS3-1
MFSD8	NM_001371591.2		c.961G>A	p.Val321Ile	missense	Exon 9 of 12	NP_001358520.1
MFSD8	NM_001371592.2		c.967G>A	p.Val323Ile	missense	Exon 9 of 12	NP_001358521.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MFSD8	ENST00000641686.2	MANE Select	c.961G>A	p.Val321Ile	missense	Exon 9 of 12	ENSP00000493218.2	Q8NHS3-1
MFSD8	ENST00000296468.8	TSL:1	c.961G>A	p.Val321Ile	missense	Exon 10 of 13	ENSP00000296468.3	Q8NHS3-1
MFSD8	ENST00000945724.1		c.949G>A	p.Val317Ile	missense	Exon 9 of 12	ENSP00000615783.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251282

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111778

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41506

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Late-infantile neuronal ceroid lipofuscinosis (1)

Neuronal ceroid lipofuscinosis 7 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.062

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.80

M_CAP

Benign

0.031

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.39

PhyloP100

0.78

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.12

REVEL

Benign

0.14

Sift

Benign

0.28

Sift4G

Benign

0.47

Polyphen

0.35

Vest4

0.19

MVP

0.68

MPC

0.081

ClinPred

0.026

GERP RS

2.4

Varity_R

0.014

gMVP

0.58

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over