rs186143284

Variant names:

• chr17-28399670-G-A
• rs186143284
• NM_080669.6:c.1366C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P456L) has been classified as Uncertain significance.

• 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
• Publications: 9 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 (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 Benign/Likely_benign. ClinVar VariationId is 235433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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.1366C>T	p.Pro456Ser	missense	Exon 5 of 5	NP_542400.2
	SARM1	NM_015077.4	MANE Select	c.*3384G>A		3_prime_UTR	Exon 9 of 9	NP_055892.2	Q6SZW1-1
	SLC46A1	NM_001242366.3		c.1282C>T	p.Pro428Ser	missense	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.1366C>T	p.Pro456Ser	missense	Exon 5 of 5	ENSP00000480703.1	Q96NT5-1
	SLC46A1	ENST00000618626.1	TSL:1	c.1282C>T	p.Pro428Ser	missense	Exon 4 of 4	ENSP00000483652.1	Q96NT5-2
	SARM1	ENST00000585482.6	TSL:1 MANE Select	c.*3384G>A		3_prime_UTR	Exon 9 of 9	ENSP00000468032.2	Q6SZW1-1

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

GnomAD2 exomes AF: 0.00311 AC: 770 AN: 247576 AF XY: 0.00301

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86256

European-Finnish (FIN) AF: 0.00698 AC: 373 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00374 AC: 4161 AN: 1111856

Other (OTH) AF: 0.00258 AC: 156 AN: 60372

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

African (AFR) AF: 0.000553 AC: 23 AN: 41562

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00566 AC: 60 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00351 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	SLC46A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.29
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.85	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs186143284; hg19: chr17-26726686; COSMIC: COSV99135084; COSMIC: COSV99135084;