17-28395709-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_080669.6(SLC46A1):c.*3947G>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 0.574 in 585,312 control chromosomes in the GnomAD database, including 98,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26918 hom., cov: 31)
  • Exomes 𝑓: 0.57 (71283 hom.)
• Consequence: SLC46A1 NM_080669.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-28395709-C-T is Benign according to our data. Variant chr17-28395709-C-T is described in ClinVar as [Benign]. Clinvar id is 322348.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC46A1	NM_080669.6	c.*3947G>A		3_prime_UTR_variant	5/5	ENST00000612814.5
SARM1	NM_015077.4	c.1924-196C>T		intron_variant		ENST00000585482.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC46A1	ENST00000612814.5	c.*3947G>A		3_prime_UTR_variant	5/5	2	NM_080669.6	P1
SARM1	ENST00000585482.6	c.1924-196C>T		intron_variant		1	NM_015077.4	P1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89672 AN: 151892 Hom.: 26908 Cov.: 31

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.618

GnomAD4 exome AF: 0.568 AC: 246180 AN: 433302 Hom.: 71283 Cov.: 5 AF XY: 0.566 AC XY: 128351 AN XY: 226822

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.621

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.531

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.582

GnomAD4 genome AF: 0.590 AC: 89724 AN: 152010 Hom.: 26918 Cov.: 31 AF XY: 0.585 AC XY: 43461 AN XY: 74282

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.613

Alfa AF: 0.558 Hom.: 4706

Bravo AF: 0.612

Asia WGS AF: 0.555 AC: 1933 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital defect of folate absorption Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.8
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs8081240; hg19: chr17-26722728;