16-48170905-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001370497.1(ABCC11):c.3761C>T(p.Thr1254Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC11 NM_001370497.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

Genes affected

ABCC11 (HGNC:14639): (ATP binding cassette subfamily C member 11) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. 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). This ABC full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. The product of this gene participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides. In addition, a SNP in this gene is responsible for determination of human earwax type. This gene and family member ABCC12 are determined to be derived by duplication and are both localized to chromosome 16q12.1. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC11	NM_001370497.1	c.3761C>T	p.Thr1254Ile	missense_variant	27/30	ENST00000356608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC11	ENST00000356608.7	c.3761C>T	p.Thr1254Ile	missense_variant	27/30	1	NM_001370497.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.3761C>T (p.T1254I) alteration is located in exon 27 (coding exon 26) of the ABCC11 gene. This alteration results from a C to T substitution at nucleotide position 3761, causing the threonine (T) at amino acid position 1254 to be replaced by an isoleucine (I). 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	Benign	0.26
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D;.;.;T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.81	L;L;L;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.71	P;B;B;B
Vest4		0.81
MutPred		0.70		Loss of methylation at K1258 (P = 0.1025);Loss of methylation at K1258 (P = 0.1025);Loss of methylation at K1258 (P = 0.1025);Loss of methylation at K1258 (P = 0.1025);
MVP		0.92
MPC		0.48
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.73
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-48204816;