chr12-51890734-G-T

Position:

• chr12-51890734-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182608.4(ANKRD33):​c.788G>T​(p.Trp263Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKRD33 NM_182608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.83

Genes affected

ANKRD33 (HGNC:13788): (ankyrin repeat domain 33) Predicted to be involved in negative regulation of transcription by RNA polymerase II and negative regulation of transcription regulatory region DNA binding activity. Predicted to act upstream of or within skeletal muscle cell differentiation. Predicted to be located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD33	NM_182608.4	c.788G>T	p.Trp263Leu	missense_variant	5/5	ENST00000301190.11	NP_872414.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD33	ENST00000301190.11	c.788G>T	p.Trp263Leu	missense_variant	5/5	2	NM_182608.4	ENSP00000301190	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 97

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 16, 2022

The c.788G>T (p.W263L) alteration is located in exon 5 (coding exon 5) of the ANKRD33 gene. This alteration results from a G to T substitution at nucleotide position 788, causing the tryptophan (W) at amino acid position 263 to be replaced by a leucine (L). 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	0.43
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-10	D;D
REVEL	Benign	0.27
Sift	Benign	0.19	T;T
Sift4G	Benign	0.44	T;T
Vest4		0.67
MutPred		0.62		.;Gain of catalytic residue at G143 (P = 0.0072);
MVP		0.64
MPC		0.77
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.72
gMVP		0.81

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

Other links and lift over

dbSNP: rs1940395383; hg19: chr12-52284518;