rs886052737

Variant names:

• chr17-28395020-G-A
• rs886052737
• NM_080669.6:c.*4636C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_080669.6(SLC46A1):​c.*4636C>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 0.00114 in 147,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 26)
  • Failed GnomAD Quality Control
• Consequence: SLC46A1 NM_080669.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.452
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (169/147846) while in subpopulation NFE AF = 0.00163 (109/66918). AF 95% confidence interval is 0.00138. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*4636C>T		3_prime_UTR	Exon 5 of 5	NP_542400.2
	SARM1	NM_015077.4	MANE Select	c.1924-885G>A		intron	N/A	NP_055892.2	Q6SZW1-1
	SLC46A1	NM_001242366.3		c.*4636C>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.*4636C>T		3_prime_UTR	Exon 5 of 5	ENSP00000480703.1	Q96NT5-1
	SARM1	ENST00000585482.6	TSL:1 MANE Select	c.1924-885G>A		intron	N/A	ENSP00000468032.2	Q6SZW1-1
	SARM1	ENST00000886313.1		c.1924-885G>A		intron	N/A	ENSP00000556372.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 169 AN: 147772 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00154

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00151

Gnomad FIN AF: 0.000215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000980

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: 0.00114 AC: 169 AN: 147846 Hom.: 0 Cov.: 26 AF XY: 0.00102 AC XY: 73 AN XY: 71826

African (AFR) AF: 0.000596 AC: 24 AN: 40268

American (AMR) AF: 0.00154 AC: 23 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.000581 AC: 2 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00151 AC: 7 AN: 4638

European-Finnish (FIN) AF: 0.000215 AC: 2 AN: 9316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00163 AC: 109 AN: 66918

Other (OTH) AF: 0.000971 AC: 2 AN: 2060

Alfa AF: 0.00219 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital defect of folate absorption (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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: rs886052737; hg19: chr17-26722039;