rs186143284

Positions:

• chr17-28399670-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080669.6(SLC46A1):​c.1366C>T​(p.Pro456Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,990 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (15 hom.)
• Consequence: SLC46A1 NM_080669.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.286

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003211528).
• BP6: Variant 17-28399670-G-A is Benign according to our data. Variant chr17-28399670-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-28399670-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00226 (344/152296) while in subpopulation NFE AF= 0.00356 (242/68032). AF 95% confidence interval is 0.00319. There are 0 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A1	NM_080669.6	c.1366C>T	p.Pro456Ser	missense_variant	5/5	ENST00000612814.5	NP_542400.2
SARM1	NM_015077.4	c.*3384G>A		3_prime_UTR_variant	9/9	ENST00000585482.6	NP_055892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A1	ENST00000612814.5	c.1366C>T	p.Pro456Ser	missense_variant	5/5	2	NM_080669.6	ENSP00000480703.1
SLC46A1	ENST00000618626.1	c.1282C>T	p.Pro428Ser	missense_variant	4/4	1		ENSP00000483652.1
SARM1	ENST00000585482.6	c.*3384G>A		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032.2
SLC46A1	ENST00000582735.1	c.249C>T	p.Phe83Phe	synonymous_variant	2/2	4		ENSP00000463339.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00311 AC: 770 AN: 247576 Hom.: 4 AF XY: 0.00301 AC XY: 405 AN XY: 134474

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00654

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00330 AC: 4819 AN: 1461694 Hom.: 15 Cov.: 31 AF XY: 0.00319 AC XY: 2316 AN XY: 727132

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00698

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74464

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00566

Gnomad4 NFE AF: 0.00356

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00366 Hom.: 4

Bravo AF: 0.00205

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00444 AC: 37

ExAC AF: 0.00346 AC: 418

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SARM1: BS2; SLC46A1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2024	Variant summary: SLC46A1 c.1366C>T (p.Pro456Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 247576 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC46A1 causing Congenital Defect Of Folate Absorption phenotype (0.0011). c.1366C>T has been reported in the literature in individuals affected with intellectual disability and individuals from general population in a case-control study for factors affecting Folate levels (Pavlkova_2012, Redin_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Defect Of Folate Absorption. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22695967, 25167861). ClinVar contains an entry for this variant (Variation ID: 235433). Based on the evidence outlined above, the variant was classified as likely benign. -

SLC46A1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.85	T;T
Polyphen		0.0	B;.
Vest4		0.047
MVP		0.25
ClinPred		0.0029	T
GERP RS		0.37
Varity_R		0.028
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186143284; hg19: chr17-26726686; COSMIC: COSV99135084; COSMIC: COSV99135084;