rs2239908

chr17-28398249-G-Achr17-28398249-G-Cchr17-28398249-G-T

Variant summary

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

The NM_015077.4(SARM1):c.*1963G>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 0.583 in 152,094 control chromosomes in the GnomAD database, including 26,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26162 hom., cov: 32)
  • Exomes 𝑓: 0.54 (12 hom.)
• Consequence: SARM1 NM_015077.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.55

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-28398249-G-A is Benign according to our data. Variant chr17-28398249-G-A is described in ClinVar as [Benign]. Clinvar id is 322384.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
SARM1	NM_015077.4	c.*1963G>A		3_prime_UTR_variant	9/9	ENST00000585482.6
SLC46A1	NM_080669.6	c.*1407C>T		3_prime_UTR_variant	5/5	ENST00000612814.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SARM1	ENST00000585482.6	c.*1963G>A		3_prime_UTR_variant	9/9	1	NM_015077.4	P1
SLC46A1	ENST00000612814.5	c.*1407C>T		3_prime_UTR_variant	5/5	2	NM_080669.6	P1
SLC46A1	ENST00000618626.1	c.*1407C>T		3_prime_UTR_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88536 AN: 151904 Hom.: 26155 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.613

GnomAD4 exome AF: 0.542 AC: 39 AN: 72 Hom.: 12 Cov.: 0 AF XY: 0.519 AC XY: 27 AN XY: 52

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.583

GnomAD4 genome AF: 0.583 AC: 88584 AN: 152022 Hom.: 26162 Cov.: 32 AF XY: 0.578 AC XY: 42924 AN XY: 74312

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.566

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.609

Alfa AF: 0.565 Hom.: 26486

Bravo AF: 0.603

Asia WGS AF: 0.559 AC: 1944 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 13, 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	-0.85
Cadd	Benign	0.21
Dann	Benign	0.52

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: rs2239908; hg19: chr17-26725265;