rs739439

Variant names:

• chr17-28396803-C-T
• rs739439
• NM_015077.4:c.*517C>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.*517C>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 0.13 in 156,128 control chromosomes in the GnomAD database, including 1,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1546 hom., cov: 33)
  • Exomes 𝑓: 0.16 (59 hom.)
• Consequence: SARM1 NM_015077.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.230
• Publications: 20 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=-0.82).
• BP6: Variant 17-28396803-C-T is Benign according to our data. Variant chr17-28396803-C-T is described in ClinVar as Benign. ClinVar VariationId is 322365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARM1	NM_015077.4	c.*517C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000585482.6	NP_055892.2
SLC46A1	NM_080669.6	c.*2853G>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.*517C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_015077.4	ENSP00000468032.2
SLC46A1	ENST00000612814.5	c.*2853G>A		3_prime_UTR_variant	Exon 5 of 5	2	NM_080669.6	ENSP00000480703.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19631 AN: 152176 Hom.: 1545 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.157 AC: 601 AN: 3834 Hom.: 59 Cov.: 0 AF XY: 0.156 AC XY: 318 AN XY: 2038

African (AFR) AF: 0.0833 AC: 3 AN: 36

American (AMR) AF: 0.0891 AC: 67 AN: 752

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 6 AN: 38

East Asian (EAS) AF: 0.0547 AC: 7 AN: 128

South Asian (SAS) AF: 0.153 AC: 29 AN: 190

European-Finnish (FIN) AF: 0.139 AC: 5 AN: 36

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.185 AC: 459 AN: 2478

Other (OTH) AF: 0.147 AC: 25 AN: 170

GnomAD4 genome AF: 0.129 AC: 19631 AN: 152294 Hom.: 1546 Cov.: 33 AF XY: 0.127 AC XY: 9489 AN XY: 74464

African (AFR) AF: 0.0481 AC: 2000 AN: 41580

American (AMR) AF: 0.114 AC: 1744 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3472

East Asian (EAS) AF: 0.0383 AC: 198 AN: 5176

South Asian (SAS) AF: 0.186 AC: 900 AN: 4830

European-Finnish (FIN) AF: 0.132 AC: 1403 AN: 10608

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12120 AN: 68006

Other (OTH) AF: 0.143 AC: 301 AN: 2112

Alfa AF: 0.169 Hom.: 3789

Bravo AF: 0.123

Asia WGS AF: 0.126 AC: 438 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	-0.82
CADD	Benign	2.0
DANN	Benign	0.47
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs739439; hg19: chr17-26723822;