NM_001371596.2:c.863C>T

Variant names:

• chr4-127932985-G-A
• rs755384900
• NM_001371596.2:c.863C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001371596.2(MFSD8):​c.863C>T​(p.Thr288Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,456,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense, splice_region
• Scores: Splicing: ADA: 0.9883
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.65
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001371596.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	NM_001371596.2	MANE Select	c.863C>T	p.Thr288Ile	missense splice_region	Exon 8 of 12	NP_001358525.1
	MFSD8	NM_001371591.2		c.863C>T	p.Thr288Ile	missense splice_region	Exon 8 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.869C>T	p.Thr290Ile	missense splice_region	Exon 8 of 12	NP_001358521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.863C>T	p.Thr288Ile	missense splice_region	Exon 8 of 12	ENSP00000493218.2
	MFSD8	ENST00000296468.8	TSL:1	c.863C>T	p.Thr288Ile	missense splice_region	Exon 9 of 13	ENSP00000296468.3
	MFSD8	ENST00000641743.1		c.863C>T	p.Thr288Met	missense	Exon 8 of 8	ENSP00000493130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251104 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1456300 Hom.: 0 Cov.: 29 AF XY: 0.0000235 AC XY: 17 AN XY: 724910

African (AFR) AF: 0.0000900 AC: 3 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1107146

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Late-infantile neuronal ceroid lipofuscinosis (1)
-	1	-	Neuronal ceroid lipofuscinosis 7 (1)
-	1	-	Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.65		Loss of glycosylation at T291 (P = 0.0453)
MVP		0.80
MPC		0.51
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.89
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.010		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: rs755384900; hg19: chr4-128854140; COSMIC: COSV56550444; COSMIC: COSV56550444;