NM_001371596.2:c.590G>A

Variant names:

• chr4-127939961-C-T
• rs28544073
• NM_001371596.2:c.590G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_001371596.2(MFSD8):​c.590G>A​(p.Gly197Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000344 in 1,613,454 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G197V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 6.59
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.014030397).
• BP6: Variant 4-127939961-C-T is Benign according to our data. Variant chr4-127939961-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198619.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00166 (252/152200) while in subpopulation AFR AF = 0.00583 (242/41538). AF 95% confidence interval is 0.00522. There are 0 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.590G>A	p.Gly197Asp	missense	Exon 6 of 12	NP_001358525.1	Q8NHS3-1
	MFSD8	NM_001371591.2		c.590G>A	p.Gly197Asp	missense	Exon 6 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.596G>A	p.Gly199Asp	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.590G>A	p.Gly197Asp	missense	Exon 6 of 12	ENSP00000493218.2	Q8NHS3-1
	MFSD8	ENST00000296468.8	TSL:1	c.590G>A	p.Gly197Asp	missense	Exon 7 of 13	ENSP00000296468.3	Q8NHS3-1
	MFSD8	ENST00000945724.1		c.578G>A	p.Gly193Asp	missense	Exon 6 of 12	ENSP00000615783.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000510 AC: 128 AN: 251174 AF XY: 0.000420

Gnomad AFR exome AF: 0.00690

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461254 Hom.: 3 Cov.: 31 AF XY: 0.000183 AC XY: 133 AN XY: 726930

African (AFR) AF: 0.00729 AC: 244 AN: 33456

American (AMR) AF: 0.000358 AC: 16 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111742

Other (OTH) AF: 0.000298 AC: 18 AN: 60366

GnomAD4 genome AF: 0.00166 AC: 252 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.00168 AC XY: 125 AN XY: 74414

African (AFR) AF: 0.00583 AC: 242 AN: 41538

American (AMR) AF: 0.000524 AC: 8 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000603 Hom.: 1

Bravo AF: 0.00222

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3472

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Neuronal ceroid lipofuscinosis 7 (2)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Late-infantile neuronal ceroid lipofuscinosis (1)
-	-	1	MFSD8-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.90
MPC		0.56
ClinPred		0.088	T
GERP RS		4.5
PromoterAI		0.0025	Neutral
Varity_R		0.73
gMVP		0.73
Mutation Taster		=38/62	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: rs28544073; hg19: chr4-128861116; COSMIC: COSV99075045; COSMIC: COSV99075045;