Genetic Variant SLCO4C1:p.Tyr659Phe (chr5-102239289-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_180991.5(SLCO4C1):c.1976A>T(p.Tyr659Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y659S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLCO4C1
NM_180991.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.66

Publications

0 publications found

Variant links:

Genes affected

SLCO4C1 (HGNC:23612): (solute carrier organic anion transporter family member 4C1) SLCO4C1 belongs to the organic anion transporter (OATP) family. OATPs are involved in the membrane transport of bile acids, conjugated steroids, thyroid hormone, eicosanoids, peptides, and numerous drugs in many tissues (Mikkaichi et al., 2004 [PubMed 14993604]).[supplied by OMIM, Mar 2008]

SLCO4C1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO4C1	NM_180991.5 link	c.1976A>T	p.Tyr659Phe	missense_variant	Exon 12 of 13	ENST00000310954.7	NP_851322.3	Q6ZQN7
SLCO4C1	XM_011543370.3 link	c.1712A>T	p.Tyr571Phe	missense_variant	Exon 11 of 12		XP_011541672.1
SLCO4C1	XM_011543372.2 link	c.1562A>T	p.Tyr521Phe	missense_variant	Exon 14 of 15		XP_011541674.1
SLCO4C1	XM_047417146.1 link	c.1562A>T	p.Tyr521Phe	missense_variant	Exon 14 of 15		XP_047273102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO4C1	ENST00000310954.7 link	c.1976A>T	p.Tyr659Phe	missense_variant	Exon 12 of 13	1	NM_180991.5	ENSP00000309741.6		Q6ZQN7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448750

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32898

American (AMR)

AF:

0.00

AC:

AN:

43124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39092

South Asian (SAS)

AF:

0.00

AC:

AN:

83278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105840

Other (OTH)

AF:

0.00

AC:

AN:

59808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.6

PhyloP100

5.7

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MutPred

0.90

Loss of catalytic residue at I658 (P = 0.0864);

MVP

0.83

MPC

0.29

ClinPred

1.0

GERP RS

5.4

Varity_R

0.67

gMVP

0.46

Mutation Taster

=82/18

polymorphism

(source)

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

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5-102239289-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over