17-28394876-G-A

Variant names:

• chr17-28394876-G-A
• rs1128161
• NM_080669.6:c.*4780C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080669.6(SLC46A1):​c.*4780C>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 0.596 in 152,000 control chromosomes in the GnomAD database, including 27,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27502 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: SLC46A1 NM_080669.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.435
• Publications: 4 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-28394876-G-A is Benign according to our data. Variant chr17-28394876-G-A is described in ClinVar as Benign. ClinVar VariationId is 322336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080669.6. 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
	SLC46A1	NM_080669.6	MANE Select	c.*4780C>T		3_prime_UTR	Exon 5 of 5	NP_542400.2
	SARM1	NM_015077.4	MANE Select	c.1924-1029G>A		intron	N/A	NP_055892.2	Q6SZW1-1
	SLC46A1	NM_001242366.3		c.*4780C>T		3_prime_UTR	Exon 4 of 4	NP_001229295.1	Q96NT5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC46A1	ENST00000612814.5	TSL:2 MANE Select	c.*4780C>T		3_prime_UTR	Exon 5 of 5	ENSP00000480703.1	Q96NT5-1
	SARM1	ENST00000585482.6	TSL:1 MANE Select	c.1924-1029G>A		intron	N/A	ENSP00000468032.2	Q6SZW1-1
	SARM1	ENST00000886313.1		c.1924-1029G>A		intron	N/A	ENSP00000556372.1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90567 AN: 151882 Hom.: 27492 Cov.: 31

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.623

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.596 AC: 90623 AN: 152000 Hom.: 27502 Cov.: 31 AF XY: 0.591 AC XY: 43880 AN XY: 74278

African (AFR) AF: 0.687 AC: 28461 AN: 41448

American (AMR) AF: 0.629 AC: 9617 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1964 AN: 3470

East Asian (EAS) AF: 0.722 AC: 3739 AN: 5180

South Asian (SAS) AF: 0.524 AC: 2517 AN: 4806

European-Finnish (FIN) AF: 0.435 AC: 4578 AN: 10536

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37739 AN: 67964

Other (OTH) AF: 0.620 AC: 1309 AN: 2112

Alfa AF: 0.434 Hom.: 1175

Bravo AF: 0.618

Asia WGS AF: 0.561 AC: 1951 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital defect of folate absorption (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		-0.43
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: rs1128161; hg19: chr17-26721895;