rs764964269

Variant names:

• chr4-127957596-G-A
• rs764964269
• NM_001371596.2:c.63-4C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001371596.2(MFSD8):​c.63-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,596,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 splice_region, intron
• Scores: Splicing: ADA: 0.00008232
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0830
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-127957596-G-A is Benign according to our data. Variant chr4-127957596-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 464779.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.63-4C>T		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.63-4C>T		splice_region_variant, intron_variant	Intron 1 of 11		NM_001371596.2	ENSP00000493218.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248430 AF XY: 0.0000298

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000381 AC: 55 AN: 1444466 Hom.: 0 Cov.: 26 AF XY: 0.0000375 AC XY: 27 AN XY: 719708

African (AFR) AF: 0.00 AC: 0 AN: 32976

American (AMR) AF: 0.00 AC: 0 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 85032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000464 AC: 51 AN: 1098216

Other (OTH) AF: 0.0000670 AC: 4 AN: 59744

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151908 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74156

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.0000547

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Benign:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.3
DANN	Benign	0.46
PhyloP100		0.083
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0040
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: rs764964269; hg19: chr4-128878751;