rs767263985

Variant names:

• chr20-765401-G-A
• NM_033409.4:c.374C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-765401-G-A
• chr20-765401-G-C
• chr20-765401-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_033409.4(SLC52A3):​c.374C>T​(p.Thr125Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.91

Genes affected

SLC52A3 (HGNC:16187): (solute carrier family 52 member 3) This gene encodes a riboflavin transporter protein that is strongly expressed in the intestine and likely plays a role in intestinal absorption of riboflavin. The protein is predicted to have eleven transmembrane domains and a cell surface localization signal in the C-terminus. Mutations at this locus have been associated with Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 20-765401-G-A is Pathogenic according to our data. Variant chr20-765401-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2583157.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.374C>T	p.Thr125Ile	missense_variant	Exon 2 of 5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.374C>T	p.Thr125Ile	missense_variant	Exon 2 of 5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 1 Pathogenic:1

-

Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_033409.4:c.374C>T (NP_212134.3:p.Thr125Ile) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr125Ile variant is novel (not in any individuals) in 1000 Genomes. The p.Thr125Ile variant is novel (not in any individuals) in gnomAD as well as in our inhouse database. There is a moderate physicochemical difference between threonine and isoleucine. The gene SLC52A3 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.25. The gene SLC52A3 contains 12 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Thr125Ile missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 125 of SLC52A3 is conserved in all mammalian species. The nucleotide c.374 in SLC52A3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In addition the clinical phenotype of the proband matches with that caused by pathogenic variants in SLC52A3. For these reasons, this variant has been classified as Uncertain Significance. (PM2 PP2 PP3 PP4_ Moderate PP1) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;T;.;T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	.;.;D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	.;.;D;D;.
Sift4G	Uncertain	0.0040	.;D;D;D;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.96, 0.97
MutPred		0.69		Loss of glycosylation at T125 (P = 0.0235);Loss of glycosylation at T125 (P = 0.0235);Loss of glycosylation at T125 (P = 0.0235);Loss of glycosylation at T125 (P = 0.0235);Loss of glycosylation at T125 (P = 0.0235);
MVP		0.91
MPC		0.92
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-746045;