21-45515870-C-G

Variant names:

• chr21-45515870-C-G
• rs58836581
• NM_194255.4:c.1564G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194255.4(SLC19A1):​c.1564G>C​(p.Asp522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,428,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D522N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SLC19A1 NM_194255.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13573161).

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.1564G>C	p.Asp522His	missense	Exon 6 of 6	NP_919231.1	P41440-1
	SLC19A1	NM_001352512.2		c.1564G>C	p.Asp522His	missense	Exon 6 of 6	NP_001339441.1	P41440-1
	SLC19A1	NM_001205207.3		c.1444G>C	p.Asp482His	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.1564G>C	p.Asp522His	missense	Exon 6 of 6	ENSP00000308895.4	P41440-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1293+9947G>C		intron	N/A	ENSP00000457278.1	H3BTQ3
	SLC19A1	ENST00000380010.8	TSL:1	c.1294-718G>C		intron	N/A	ENSP00000369347.4	P41440-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000973 AC: 2 AN: 205522 AF XY: 0.0000179

Gnomad AFR exome AF: 0.0000730

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 39 AN: 1428072 Hom.: 0 Cov.: 36 AF XY: 0.0000198 AC XY: 14 AN XY: 707000

African (AFR) AF: 0.0000306 AC: 1 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 40316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39064

South Asian (SAS) AF: 0.00 AC: 0 AN: 81892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.0000338 AC: 37 AN: 1094498

Other (OTH) AF: 0.0000170 AC: 1 AN: 58794

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.17
MutPred		0.070		Loss of helix (P = 0.0558)
MVP		0.31
MPC		0.55
ClinPred		0.27	T
GERP RS		2.8
Varity_R		0.089
gMVP		0.18
Mutation Taster		=96/4	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: rs58836581; hg19: chr21-46935784;