rs80338770

Variant names:

• chr17-28405360-G-A
• rs80338770
• NM_080669.6:c.337C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-28405360-G-A
• chr17-28405360-G-T
• chr17-28405360-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_080669.6(SLC46A1):​c.337C>T​(p.Arg113Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,433,096 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. R113S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC46A1 NM_080669.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.31
• Publications: 12 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]

SLC46A1 Gene-Disease associations (from GenCC):

• hereditary folate malabsorption

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P, Ambry Genetics

ENSG00000265254 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-28405360-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 852.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-28405360-G-A is Pathogenic according to our data. Variant chr17-28405360-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 855.Status of the report is no_assertion_criteria_provided, 0 stars.

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.337C>T	p.Arg113Cys	missense	Exon 2 of 5	NP_542400.2
	SLC46A1	NM_001242366.3		c.337C>T	p.Arg113Cys	missense	Exon 2 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.337C>T	p.Arg113Cys	missense	Exon 2 of 5	ENSP00000480703.1	Q96NT5-1
	SLC46A1	ENST00000618626.1	TSL:1	c.337C>T	p.Arg113Cys	missense	Exon 2 of 4	ENSP00000483652.1	Q96NT5-2
	SLC46A1	ENST00000584995.5	TSL:3	c.115C>T	p.Arg39Cys	missense	Exon 3 of 3	ENSP00000464190.1	J3QRF7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000507 AC: 1 AN: 197184 AF XY: 0.00000936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433096 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710276

African (AFR) AF: 0.00 AC: 0 AN: 32826

American (AMR) AF: 0.0000249 AC: 1 AN: 40110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 38058

South Asian (SAS) AF: 0.00 AC: 0 AN: 82052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098714

Other (OTH) AF: 0.00 AC: 0 AN: 59322

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.68	D
PhyloP100		6.3
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of methylation at R113 (P = 0.0666)
MVP		0.91
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs80338770; hg19: chr17-26732378;