11-119158594-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_022169.5(ABCG4):​c.1205T>C​(p.Ile402Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,090 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ABCG4
NM_022169.5 missense

Scores

4
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01
Variant links:
Genes affected
ABCG4 (HGNC:13884): (ATP binding cassette subfamily G member 4) The protein encoded by this gene is a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein is a member of the White subfamily and plays an important role in cellular cholesterol homeostasis. This protein functions as either a homodimer or as a heterodimer with another ABC subfamily protein such as ABCG1. [provided by RefSeq, Jan 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCG4NM_022169.5 linkc.1205T>C p.Ile402Thr missense_variant Exon 11 of 15 ENST00000619701.5 NP_071452.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCG4ENST00000619701.5 linkc.1205T>C p.Ile402Thr missense_variant Exon 11 of 15 1 NM_022169.5 ENSP00000481728.1 Q9H172-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251492
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 06, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1205T>C (p.I402T) alteration is located in exon 11 (coding exon 10) of the ABCG4 gene. This alteration results from a T to C substitution at nucleotide position 1205, causing the isoleucine (I) at amino acid position 402 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D;D;D
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
.;.;D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.7
L;L;L
PrimateAI
Uncertain
0.79
T
Sift4G
Uncertain
0.047
D;D;D
Polyphen
0.75
P;P;P
Vest4
0.95
MutPred
0.69
Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);
MVP
0.77
ClinPred
0.77
D
GERP RS
5.6
Varity_R
0.31
gMVP
0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs774948961; hg19: chr11-119029304; API