rs17719944

Variant names:

• chr17-28402435-A-G
• rs17719944
• NM_015077.4:c.*6149A>G

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.*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
• Publications: 5 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=-0.86).
• BP6: Variant 17-28402435-A-G is Benign according to our data. Variant chr17-28402435-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015077.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SARM1	NM_015077.4	MANE Select	c.*6149A>G		3_prime_UTR	Exon 9 of 9	NP_055892.2
	SLC46A1	NM_080669.6	MANE Select	c.1082-114T>C		intron	N/A	NP_542400.2
	SLC46A1	NM_001242366.3		c.1082-1669T>C		intron	N/A	NP_001229295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SARM1	ENST00000585482.6	TSL:1 MANE Select	c.*6149A>G		3_prime_UTR	Exon 9 of 9	ENSP00000468032.2
	SLC46A1	ENST00000612814.5	TSL:2 MANE Select	c.1082-114T>C		intron	N/A	ENSP00000480703.1
	SLC46A1	ENST00000618626.1	TSL:1	c.1082-1669T>C		intron	N/A	ENSP00000483652.1

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

African (AFR) AF: 0.0146 AC: 258 AN: 17654

American (AMR) AF: 0.0354 AC: 1072 AN: 30256

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 1913 AN: 17612

East Asian (EAS) AF: 0.000127 AC: 4 AN: 31480

South Asian (SAS) AF: 0.0227 AC: 1250 AN: 55024

European-Finnish (FIN) AF: 0.0678 AC: 2691 AN: 39684

Middle Eastern (MID) AF: 0.0618 AC: 248 AN: 4010

European-Non Finnish (NFE) AF: 0.0902 AC: 40717 AN: 451540

Other (OTH) AF: 0.0661 AC: 2201 AN: 33282

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

African (AFR) AF: 0.0157 AC: 654 AN: 41590

American (AMR) AF: 0.0487 AC: 745 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4834

European-Finnish (FIN) AF: 0.0685 AC: 728 AN: 10622

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0853 AC: 5803 AN: 68008

Other (OTH) AF: 0.0638 AC: 135 AN: 2116

Alfa AF: 0.0794 Hom.: 839

Bravo AF: 0.0539

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		0.75
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: rs17719944; hg19: chr17-26729453;