NM_001371596.2:c.1153G>C

Variant names:

• chr4-127921721-C-G
• rs11098943
• NM_001371596.2:c.1153G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371596.2(MFSD8):​c.1153G>C​(p.Gly385Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,614,010 control chromosomes in the GnomAD database, including 575 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G385G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (81 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (494 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.252
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022776723).
• BP6: Variant 4-127921721-C-G is Benign according to our data. Variant chr4-127921721-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0922 is higher than 0.05.

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.1153G>C	p.Gly385Arg	missense	Exon 11 of 12	NP_001358525.1
	MFSD8	NM_001371591.2		c.1153G>C	p.Gly385Arg	missense	Exon 11 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.1159G>C	p.Gly387Arg	missense	Exon 11 of 12	NP_001358521.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.1153G>C	p.Gly385Arg	missense	Exon 11 of 12	ENSP00000493218.2
	MFSD8	ENST00000296468.8	TSL:1	c.1153G>C	p.Gly385Arg	missense	Exon 12 of 13	ENSP00000296468.3
	MFSD8	ENST00000945724.1		c.1141G>C	p.Gly381Arg	missense	Exon 11 of 12	ENSP00000615783.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152034 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0252 AC: 6335 AN: 251292 AF XY: 0.0202

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00671 AC: 9804 AN: 1461858 Hom.: 494 Cov.: 32 AF XY: 0.00610 AC XY: 4433 AN XY: 727226

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.113 AC: 5056 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0903 AC: 3586 AN: 39696

South Asian (SAS) AF: 0.00250 AC: 216 AN: 86254

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1112000

Other (OTH) AF: 0.00919 AC: 555 AN: 60394

GnomAD4 genome AF: 0.0122 AC: 1853 AN: 152152 Hom.: 81 Cov.: 32 AF XY: 0.0134 AC XY: 997 AN XY: 74372

African (AFR) AF: 0.00400 AC: 166 AN: 41498

American (AMR) AF: 0.0701 AC: 1071 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0993 AC: 514 AN: 5178

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4816

European-Finnish (FIN) AF: 0.000944 AC: 10 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68002

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.00293 Hom.: 10

Bravo AF: 0.0177

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0205 AC: 2490

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Neuronal ceroid lipofuscinosis 7 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Late-infantile neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.63
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.25
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.23
Sift	Benign	0.56	T
Sift4G	Benign	0.49	T
Polyphen		0.20	B
Vest4		0.15
MPC		0.12
ClinPred		0.00014	T
GERP RS		-1.1
Varity_R		0.055
gMVP		0.96
Mutation Taster		=99/1	polymorphism (auto)

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: rs11098943; hg19: chr4-128842876; COSMIC: COSV56552591; COSMIC: COSV56552591;