chr17-28402410-C-T

Variant names:

• chr17-28402410-C-T
• rs4795436
• NM_015077.4:c.*6124C>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.*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
• Publications: 12 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=-0.88).
• BP6: Variant 17-28402410-C-T is Benign according to our data. Variant chr17-28402410-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
SARM1	NM_015077.4	c.*6124C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000585482.6	NP_055892.2
SLC46A1	NM_080669.6	c.1082-89G>A		intron_variant	Intron 2 of 4	ENST00000612814.5	NP_542400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARM1	ENST00000585482.6	c.*6124C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_015077.4	ENSP00000468032.2
SLC46A1	ENST00000612814.5	c.1082-89G>A		intron_variant	Intron 2 of 4	2	NM_080669.6	ENSP00000480703.1
SLC46A1	ENST00000618626.1	c.1082-1644G>A		intron_variant	Intron 2 of 3	1		ENSP00000483652.1
SLC46A1	ENST00000582735.1	c.205+2206G>A		intron_variant	Intron 1 of 1	4		ENSP00000463339.1

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

African (AFR) AF: 0.859 AC: 19799 AN: 23062

American (AMR) AF: 0.920 AC: 32047 AN: 34838

Ashkenazi Jewish (ASJ) AF: 0.964 AC: 20848 AN: 21618

East Asian (EAS) AF: 0.817 AC: 27808 AN: 34038

South Asian (SAS) AF: 0.872 AC: 59682 AN: 68438

European-Finnish (FIN) AF: 0.899 AC: 41202 AN: 45830

Middle Eastern (MID) AF: 0.938 AC: 4515 AN: 4812

European-Non Finnish (NFE) AF: 0.963 AC: 652495 AN: 677678

Other (OTH) AF: 0.932 AC: 40193 AN: 43106

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

African (AFR) AF: 0.861 AC: 35765 AN: 41552

American (AMR) AF: 0.928 AC: 14215 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3349 AN: 3472

East Asian (EAS) AF: 0.769 AC: 3984 AN: 5182

South Asian (SAS) AF: 0.848 AC: 4098 AN: 4834

European-Finnish (FIN) AF: 0.893 AC: 9487 AN: 10626

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.959 AC: 65267 AN: 68032

Other (OTH) AF: 0.920 AC: 1945 AN: 2114

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.029
DANN	Benign	0.45
PhyloP100		-2.6
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: rs4795436; hg19: chr17-26729428;