17-28395020-G-GAA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_080669.6(SLC46A1):c.*4635_*4636insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: SLC46A1 NM_080669.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.395

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0011 (163/147702) while in subpopulation AMR AF= 0.00134 (20/14894). AF 95% confidence interval is 0.00089. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC46A1	NM_080669.6	c.*4635_*4636insTT		3_prime_UTR_variant	5/5	ENST00000612814.5
SARM1	NM_015077.4	c.1924-874_1924-873dup		intron_variant		ENST00000585482.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC46A1	ENST00000612814.5	c.*4635_*4636insTT		3_prime_UTR_variant	5/5	2	NM_080669.6	P1
SARM1	ENST00000585482.6	c.1924-874_1924-873dup		intron_variant		1	NM_015077.4	P1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 162 AN: 147628 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00134

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.000645

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00110 AC: 163 AN: 147702 Hom.: 0 Cov.: 0 AF XY: 0.00132 AC XY: 95 AN XY: 71748

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000588

Gnomad4 SAS AF: 0.000647

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00146

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital defect of folate absorption Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34879232; hg19: chr17-26722039;