NM_017435.5:c.251T>C

Variant names:

• chr12-20701439-T-C
• rs145845267
• NM_017435.5:c.251T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017435.5(SLCO1C1):​c.251T>C​(p.Ile84Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,513,456 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLCO1C1 NM_017435.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65
• Publications: 1 publications found

Genes affected

SLCO1C1 (HGNC:13819): (solute carrier organic anion transporter family member 1C1) This gene encodes a member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of thyroid hormones in brain tissues. This protein has particularly high affinity for the thyroid hormones thyroxine, tri-iodothyronine and reverse tri-iodothyronine. Polymorphisms in the gene encoding this protein may be associated with fatigue and depression in patients suffering from hyperthyroidism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

SLCO1C1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017435.5. 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
	SLCO1C1	NM_017435.5	MANE Select	c.251T>C	p.Ile84Thr	missense	Exon 3 of 15	NP_059131.1	Q9NYB5-1
	SLCO1C1	NM_001145946.2		c.251T>C	p.Ile84Thr	missense	Exon 4 of 16	NP_001139418.1	Q9NYB5-3
	SLCO1C1	NM_001145945.2		c.251T>C	p.Ile84Thr	missense	Exon 4 of 15	NP_001139417.1	Q9NYB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1C1	ENST00000266509.7	TSL:1 MANE Select	c.251T>C	p.Ile84Thr	missense	Exon 3 of 15	ENSP00000266509.2	Q9NYB5-1
	SLCO1C1	ENST00000539415.5	TSL:1	n.129+1734T>C		intron	N/A	ENSP00000437399.1	F5H6S4
	SLCO1C1	ENST00000545604.5	TSL:2	c.251T>C	p.Ile84Thr	missense	Exon 4 of 16	ENSP00000444149.1	Q9NYB5-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 235718 AF XY: 0.0000157

Gnomad AFR exome AF: 0.000265

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: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 15 AN: 1361426 Hom.: 0 Cov.: 31 AF XY: 0.0000105 AC XY: 7 AN XY: 668792

African (AFR) AF: 0.0000318 AC: 1 AN: 31480

American (AMR) AF: 0.0000241 AC: 1 AN: 41412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23808

East Asian (EAS) AF: 0.00 AC: 0 AN: 37626

South Asian (SAS) AF: 0.00 AC: 0 AN: 71630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.0000115 AC: 12 AN: 1045290

Other (OTH) AF: 0.0000182 AC: 1 AN: 55076

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74262

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.74
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.86
Mutation Taster		=25/75	disease causing

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: rs145845267; hg19: chr12-20854373;