rs80338773

Positions:

chr17-28402277-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_080669.6(SLC46A1):c.1126C>T(p.Arg376Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SLC46A1
NM_080669.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:2

Conservation

PhyloP100: 4.99

Variant links:

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]

SLC46A1 links:

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]

SARM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a mutagenesis_site Abolishes folate uptake. (size 0) in uniprot entity PCFT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_080669.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-28402276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65749.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=2, Pathogenic=2, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 17-28402277-G-A is Pathogenic according to our data. Variant chr17-28402277-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 854.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-28402277-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC46A1	NM_080669.6 linkuse as main transcript	c.1126C>T	p.Arg376Trp	missense_variant	3/5	ENST00000612814.5
SARM1	NM_015077.4 linkuse as main transcript	c.*5991G>A		3_prime_UTR_variant	9/9	ENST00000585482.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC46A1	ENST00000612814.5 linkuse as main transcript	c.1126C>T	p.Arg376Trp	missense_variant	3/5	2	NM_080669.6	P1	Q96NT5-1
SARM1	ENST00000585482.6 linkuse as main transcript	c.*5991G>A		3_prime_UTR_variant	9/9	1	NM_015077.4	P1	Q6SZW1-1
SLC46A1	ENST00000618626.1 linkuse as main transcript	c.1082-1511C>T		intron_variant		1			Q96NT5-2
SLC46A1	ENST00000582735.1 linkuse as main transcript	c.206+2339C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

246220

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

133784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000263

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461244

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital defect of folate absorption

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2007	- -

not provided

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.49

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.54

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MutPred

0.92

Gain of ubiquitination at K378 (P = 0.0467);

MVP

0.54

ClinPred

0.94

GERP RS

5.7

Varity_R

0.89

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over