21-45516062-A-T

Variant names:

• chr21-45516062-A-T
• rs58227024
• NM_194255.4:c.1372T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_194255.4(SLC19A1):​c.1372T>A​(p.Cys458Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C458G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC19A1 NM_194255.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.503
• Publications: 0 publications found

Genes affected

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

SLC19A1 Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• immunodeficiency 114, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• megaloblastic anemia, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.270608).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194255.4. 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
	SLC19A1	NM_194255.4	MANE Select	c.1372T>A	p.Cys458Ser	missense	Exon 6 of 6	NP_919231.1	P41440-1
	SLC19A1	NM_001352512.2		c.1372T>A	p.Cys458Ser	missense	Exon 6 of 6	NP_001339441.1	P41440-1
	SLC19A1	NM_001205207.3		c.1252T>A	p.Cys418Ser	missense	Exon 5 of 5	NP_001192136.1	P41440-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.1372T>A	p.Cys458Ser	missense	Exon 6 of 6	ENSP00000308895.4	P41440-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1293+9755T>A		intron	N/A	ENSP00000457278.1	H3BTQ3
	SLC19A1	ENST00000380010.8	TSL:1	c.1294-910T>A		intron	N/A	ENSP00000369347.4	P41440-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438874 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 713544

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 39540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.00 AC: 0 AN: 38940

South Asian (SAS) AF: 0.00 AC: 0 AN: 83126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102920

Other (OTH) AF: 0.00 AC: 0 AN: 59658

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.32
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.50
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.047	B
Vest4		0.058
MutPred		0.79		Gain of disorder (P = 0.0018)
MVP		0.10
MPC		0.14
ClinPred		0.12	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.14
Mutation Taster		=91/9	polymorphism

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: rs58227024; hg19: chr21-46935976;