rs571950296

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001371596.2(MFSD8):c.864-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000106 in 1,598,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.72

Publications

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

MFSD8 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001371596.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0867052 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-127930818-C-T is Pathogenic according to our data. Variant chr4-127930818-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1067690.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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MFSD8	NM_001371596.2	MANE Select	c.864-1G>A	splice_acceptor intron	N/A	NP_001358525.1	Q8NHS3-1
MFSD8	NM_001371591.2		c.864-1G>A	splice_acceptor intron	N/A	NP_001358520.1
MFSD8	NM_001371592.2		c.870-1G>A	splice_acceptor intron	N/A	NP_001358521.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MFSD8	ENST00000641686.2	MANE Select	c.864-1G>A	splice_acceptor intron	N/A	ENSP00000493218.2	Q8NHS3-1
MFSD8	ENST00000296468.8	TSL:1	c.864-1G>A	splice_acceptor intron	N/A	ENSP00000296468.3	Q8NHS3-1
MFSD8	ENST00000945724.1		c.852-1G>A	splice_acceptor intron	N/A	ENSP00000615783.1

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

151218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000898

AC:

AN:

1447180

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

719066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32806

American (AMR)

AF:

0.00

AC:

AN:

42700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25694

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.00

AC:

AN:

81772

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1106246

Other (OTH)

AF:

0.00

AC:

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.0000264

AC:

AN:

151336

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73886

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41258

American (AMR)

AF:

0.0000658

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis 7 (2)

Late-infantile neuronal ceroid lipofuscinosis (1)

Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.7

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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