4-127930822-GAAA-GAA

Variant names:

• chr4-127930822-GA-G
• rs200526922
• NM_001371596.2:c.864-6delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001371596.2(MFSD8):​c.864-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,549,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.93
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 4-127930822-GA-G is Benign according to our data. Variant chr4-127930822-GA-G is described in ClinVar as Benign. ClinVar VariationId is 696429.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	NM_001371596.2	MANE Select	c.864-6delT		splice_region intron	N/A	NP_001358525.1	Q8NHS3-1
	MFSD8	NM_001371591.2		c.864-6delT		splice_region intron	N/A	NP_001358520.1
	MFSD8	NM_001371592.2		c.870-6delT		splice_region intron	N/A	NP_001358521.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.864-6delT		splice_region intron	N/A	ENSP00000493218.2	Q8NHS3-1
	MFSD8	ENST00000296468.8	TSL:1	c.864-6delT		splice_region intron	N/A	ENSP00000296468.3	Q8NHS3-1
	MFSD8	ENST00000945724.1		c.852-6delT		splice_region intron	N/A	ENSP00000615783.1

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 17 AN: 149130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000526 AC: 107 AN: 203414 AF XY: 0.000487

Gnomad AFR exome AF: 0.000149

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000517

Gnomad EAS exome AF: 0.000138

Gnomad FIN exome AF: 0.000411

Gnomad NFE exome AF: 0.000592

Gnomad OTH exome AF: 0.000425

GnomAD4 exome AF: 0.000275 AC: 385 AN: 1400206 Hom.: 0 Cov.: 30 AF XY: 0.000278 AC XY: 193 AN XY: 695244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000350 AC: 11 AN: 31386

American (AMR) AF: 0.000502 AC: 20 AN: 39868

Ashkenazi Jewish (ASJ) AF: 0.000204 AC: 5 AN: 24570

East Asian (EAS) AF: 0.0000529 AC: 2 AN: 37828

South Asian (SAS) AF: 0.000283 AC: 22 AN: 77806

European-Finnish (FIN) AF: 0.000387 AC: 20 AN: 51644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.000273 AC: 293 AN: 1074080

Other (OTH) AF: 0.000208 AC: 12 AN: 57566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000114 AC: 17 AN: 149130 Hom.: 0 Cov.: 32 AF XY: 0.0000962 AC XY: 7 AN XY: 72732

African (AFR) AF: 0.000148 AC: 6 AN: 40608

American (AMR) AF: 0.00 AC: 0 AN: 14936

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.000203 AC: 2 AN: 9874

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

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67158

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MFSD8-related disorder (1)
-	-	1	Neuronal ceroid lipofuscinosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs200526922; hg19: chr4-128851977; COSMIC: COSV56552605; COSMIC: COSV56552605;