17-28396594-G-T

Variant names:

• chr17-28396594-G-T
• rs2239911
• NM_015077.4:c.*308G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015077.4(SARM1):​c.*308G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 369,682 control chromosomes in the GnomAD database, including 56,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21369 hom., cov: 32)
  • Exomes 𝑓: 0.56 (34645 hom.)
• Consequence: SARM1 NM_015077.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.247
• Publications: 14 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-28396594-G-T is Benign according to our data. Variant chr17-28396594-G-T is described in CliVar as Benign. Clinvar id is 322361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARM1	NM_015077.4	c.*308G>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000585482.6	NP_055892.2
SLC46A1	NM_080669.6	c.*3062C>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000612814.5	NP_542400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARM1	ENST00000585482.6	c.*308G>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_015077.4	ENSP00000468032.2
SLC46A1	ENST00000612814.5	c.*3062C>A		3_prime_UTR_variant	Exon 5 of 5	2	NM_080669.6	ENSP00000480703.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79724 AN: 151866 Hom.: 21378 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.575

GnomAD4 exome AF: 0.560 AC: 121921 AN: 217698 Hom.: 34645 Cov.: 2 AF XY: 0.560 AC XY: 62612 AN XY: 111846

African (AFR) AF: 0.442 AC: 3286 AN: 7434

American (AMR) AF: 0.605 AC: 5386 AN: 8906

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 4085 AN: 7298

East Asian (EAS) AF: 0.752 AC: 11017 AN: 14652

South Asian (SAS) AF: 0.531 AC: 10535 AN: 19846

European-Finnish (FIN) AF: 0.456 AC: 5646 AN: 12372

Middle Eastern (MID) AF: 0.609 AC: 648 AN: 1064

European-Non Finnish (NFE) AF: 0.556 AC: 73799 AN: 132772

Other (OTH) AF: 0.563 AC: 7519 AN: 13354

GnomAD4 genome AF: 0.525 AC: 79740 AN: 151984 Hom.: 21369 Cov.: 32 AF XY: 0.521 AC XY: 38694 AN XY: 74332

African (AFR) AF: 0.437 AC: 18108 AN: 41458

American (AMR) AF: 0.607 AC: 9285 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1960 AN: 3466

East Asian (EAS) AF: 0.721 AC: 3709 AN: 5142

South Asian (SAS) AF: 0.523 AC: 2523 AN: 4824

European-Finnish (FIN) AF: 0.433 AC: 4592 AN: 10594

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37672 AN: 67912

Other (OTH) AF: 0.571 AC: 1206 AN: 2112

Alfa AF: 0.538 Hom.: 4238

Bravo AF: 0.539

Asia WGS AF: 0.549 AC: 1910 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital defect of folate absorption Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.74
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs2239911; hg19: chr17-26723613;