17-28395585-C-T

Variant names:

• chr17-28395585-C-T
• rs908290461
• NM_080669.6:c.*4071G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080669.6(SLC46A1):​c.*4071G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 272,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SLC46A1 NM_080669.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.141
• Publications: 0 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]

SARM1 (HGNC:17074): (sterile alpha and TIR motif containing 1) Enables NAD+ nucleotidase, cyclic ADP-ribose generating and identical protein binding activity. Involved in NAD catabolic process; positive regulation of neuron death; and response to axon injury. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC46A1	NM_080669.6	c.*4071G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000612814.5	NP_542400.2
SARM1	NM_015077.4	c.1924-320C>T		intron_variant	Intron 7 of 8	ENST00000585482.6	NP_055892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC46A1	ENST00000612814.5	c.*4071G>A		3_prime_UTR_variant	Exon 5 of 5	2	NM_080669.6	ENSP00000480703.1
SARM1	ENST00000585482.6	c.1924-320C>T		intron_variant	Intron 7 of 8	1	NM_015077.4	ENSP00000468032.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152134 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: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 20 AN: 120622 Hom.: 0 Cov.: 0 AF XY: 0.000175 AC XY: 11 AN XY: 62756

African (AFR) AF: 0.00 AC: 0 AN: 4502

American (AMR) AF: 0.00 AC: 0 AN: 5694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3672

East Asian (EAS) AF: 0.00 AC: 0 AN: 7052

South Asian (SAS) AF: 0.00 AC: 0 AN: 13364

European-Finnish (FIN) AF: 0.000195 AC: 1 AN: 5136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 512

European-Non Finnish (NFE) AF: 0.000244 AC: 18 AN: 73788

Other (OTH) AF: 0.000145 AC: 1 AN: 6902

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital defect of folate absorption Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		0.14

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: rs908290461; hg19: chr17-26722604;