chr17-28405909-CGG-C

Variant names:

• chr17-28405909-CGG-C
• rs397515391
• NM_080669.6:c.204_205delCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_080669.6(SLC46A1):​c.204_205delCC​(p.Asn68LysfsTer96) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,451,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SLC46A1 NM_080669.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.92
• Publications: 6 publications found

Genes affected

SLC46A1 (HGNC:30521): (solute carrier family 46 member 1) This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

SLC46A1 Gene-Disease associations (from GenCC):

• hereditary folate malabsorption

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ENSG00000265254 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-28405909-CGG-C is Pathogenic according to our data. Variant chr17-28405909-CGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30924.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080669.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC46A1	NM_080669.6	MANE Select	c.204_205delCC	p.Asn68LysfsTer96	frameshift	Exon 1 of 5	NP_542400.2
	SLC46A1	NM_001242366.3		c.204_205delCC	p.Asn68LysfsTer96	frameshift	Exon 1 of 4	NP_001229295.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC46A1	ENST00000612814.5	TSL:2 MANE Select	c.204_205delCC	p.Asn68LysfsTer96	frameshift	Exon 1 of 5	ENSP00000480703.1
	SLC46A1	ENST00000618626.1	TSL:1	c.204_205delCC	p.Asn68LysfsTer96	frameshift	Exon 1 of 4	ENSP00000483652.1
	SLC46A1	ENST00000582590.1	TSL:2	n.258_259delCC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451228 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 721054

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 84460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4966

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108090

Other (OTH) AF: 0.0000167 AC: 1 AN: 59888

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital defect of folate absorption Pathogenic:1

May 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=15/185	disease causing (ClinVar)

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: rs397515391; hg19: chr17-26732927;