rs17719944

Positions:

• chr17-28402435-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015077.4(SARM1):​c.*6149A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 832,880 control chromosomes in the GnomAD database, including 2,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (333 hom., cov: 33)
  • Exomes 𝑓: 0.074 (2214 hom.)
• Consequence: SARM1 NM_015077.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.748

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-28402435-A-G is Benign according to our data. Variant chr17-28402435-A-G is described in ClinVar as [Benign]. Clinvar id is 1261077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARM1	NM_015077.4	c.*6149A>G		3_prime_UTR_variant	9/9	ENST00000585482.6	NP_055892.2
SLC46A1	NM_080669.6	c.1082-114T>C		intron_variant		ENST00000612814.5	NP_542400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SARM1	ENST00000585482.6	c.*6149A>G		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032	P1
SLC46A1	ENST00000612814.5	c.1082-114T>C		intron_variant		2	NM_080669.6	ENSP00000480703	P1
SLC46A1	ENST00000618626.1	c.1082-1669T>C		intron_variant		1		ENSP00000483652
SLC46A1	ENST00000582735.1	c.206+2181T>C		intron_variant		4		ENSP00000463339

Frequencies

GnomAD3 genomes AF: 0.0569 AC: 8657 AN: 152220 Hom.: 332 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.0640

GnomAD4 exome AF: 0.0740 AC: 50354 AN: 680542 Hom.: 2214 Cov.: 9 AF XY: 0.0720 AC XY: 25291 AN XY: 351348

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.0902

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0568 AC: 8651 AN: 152338 Hom.: 333 Cov.: 33 AF XY: 0.0554 AC XY: 4128 AN XY: 74502

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.0853

Gnomad4 OTH AF: 0.0638

Alfa AF: 0.0828 Hom.: 681

Bravo AF: 0.0539

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.68

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: rs17719944; hg19: chr17-26729453;