17-28402410-C-T

Position:

• chr17-28402410-C-T

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.*6124C>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 0.939 in 1,105,748 control chromosomes in the GnomAD database, including 488,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63909 hom., cov: 34)
  • Exomes 𝑓: 0.94 (424472 hom.)
• Consequence: SARM1 NM_015077.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.61

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=-0.88).
• BP6: Variant 17-28402410-C-T is Benign according to our data. Variant chr17-28402410-C-T is described in ClinVar as [Benign]. Clinvar id is 1248777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARM1	NM_015077.4	c.*6124C>T		3_prime_UTR_variant	9/9	ENST00000585482.6	NP_055892.2
SLC46A1	NM_080669.6	c.1082-89G>A		intron_variant		ENST00000612814.5	NP_542400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SARM1	ENST00000585482.6	c.*6124C>T		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032	P1
SLC46A1	ENST00000612814.5	c.1082-89G>A		intron_variant		2	NM_080669.6	ENSP00000480703	P1
SLC46A1	ENST00000618626.1	c.1082-1644G>A		intron_variant		1		ENSP00000483652
SLC46A1	ENST00000582735.1	c.206+2206G>A		intron_variant		4		ENSP00000463339

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139179 AN: 152210 Hom.: 63871 Cov.: 34

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.963

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.922

GnomAD4 exome AF: 0.942 AC: 898589 AN: 953420 Hom.: 424472 Cov.: 12 AF XY: 0.940 AC XY: 457421 AN XY: 486422

Gnomad4 AFR exome AF: 0.859

Gnomad4 AMR exome AF: 0.920

Gnomad4 ASJ exome AF: 0.964

Gnomad4 EAS exome AF: 0.817

Gnomad4 SAS exome AF: 0.872

Gnomad4 FIN exome AF: 0.899

Gnomad4 NFE exome AF: 0.963

Gnomad4 OTH exome AF: 0.932

GnomAD4 genome AF: 0.914 AC: 139271 AN: 152328 Hom.: 63909 Cov.: 34 AF XY: 0.909 AC XY: 67714 AN XY: 74480

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.928

Gnomad4 ASJ AF: 0.965

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.848

Gnomad4 FIN AF: 0.893

Gnomad4 NFE AF: 0.959

Gnomad4 OTH AF: 0.920

Alfa AF: 0.943 Hom.: 15080

Bravo AF: 0.917

Asia WGS AF: 0.794 AC: 2764 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	-0.88
CADD	Benign	0.029
DANN	Benign	0.45

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: rs4795436; hg19: chr17-26729428;