chr4-127930822-G-GA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001371596.2(MFSD8):​c.864-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,534,934 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: MFSD8 NM_001371596.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 4-127930822-G-GA is Benign according to our data. Variant chr4-127930822-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 464782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.864-6dupT		splice_region intron	N/A	NP_001358525.1	Q8NHS3-1
	MFSD8	NM_001371591.2		c.864-6dupT		splice_region intron	N/A	NP_001358520.1
	MFSD8	NM_001371592.2		c.870-6dupT		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.864-6_864-5insT		splice_region intron	N/A	ENSP00000493218.2	Q8NHS3-1
	MFSD8	ENST00000296468.8	TSL:1	c.864-6_864-5insT		splice_region intron	N/A	ENSP00000296468.3	Q8NHS3-1
	MFSD8	ENST00000945724.1		c.852-6_852-5insT		splice_region intron	N/A	ENSP00000615783.1

Frequencies

GnomAD3 genomes AF: 0.000456 AC: 68 AN: 149116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000745

Gnomad OTH AF: 0.000976

GnomAD2 exomes AF: 0.00123 AC: 251 AN: 203414 AF XY: 0.00116

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000963

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00146 AC: 2029 AN: 1385708 Hom.: 2 Cov.: 30 AF XY: 0.00136 AC XY: 938 AN XY: 688016

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

African (AFR) AF: 0.00309 AC: 96 AN: 31030

American (AMR) AF: 0.00207 AC: 82 AN: 39522

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 26 AN: 24308

East Asian (EAS) AF: 0.000695 AC: 26 AN: 37426

South Asian (SAS) AF: 0.00230 AC: 177 AN: 77082

European-Finnish (FIN) AF: 0.000391 AC: 20 AN: 51164

Middle Eastern (MID) AF: 0.00203 AC: 11 AN: 5424

European-Non Finnish (NFE) AF: 0.00141 AC: 1497 AN: 1062820

Other (OTH) AF: 0.00165 AC: 94 AN: 56932

⚠️ 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: 0.000469 AC: 70 AN: 149226 Hom.: 0 Cov.: 32 AF XY: 0.000453 AC XY: 33 AN XY: 72840

African (AFR) AF: 0.00138 AC: 56 AN: 40722

American (AMR) AF: 0.0000669 AC: 1 AN: 14956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5108

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000745 AC: 5 AN: 67150

Other (OTH) AF: 0.00193 AC: 4 AN: 2072

Alfa AF: 0.00422 Hom.: 0

Bravo AF: 0.000563

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis 7 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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: rs200526922; hg19: chr4-128851977; COSMIC: COSV104408444; COSMIC: COSV104408444;