12-110027746-C-T

Position:

• chr12-110027746-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033121.2(ANKRD13A):​c.925C>T​(p.His309Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD13A NM_033121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

Genes affected

ANKRD13A (HGNC:21268): (ankyrin repeat domain 13A) Enables ubiquitin-dependent protein binding activity. Involved in negative regulation of protein localization to endosome and negative regulation of receptor internalization. Located in late endosome; perinuclear region of cytoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

C12orf76 (HGNC:33790): (chromosome 12 open reading frame 76) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40867954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD13A	NM_033121.2	c.925C>T	p.His309Tyr	missense_variant	9/15	ENST00000261739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD13A	ENST00000261739.9	c.925C>T	p.His309Tyr	missense_variant	9/15	1	NM_033121.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Apr 25, 2023

The c.925C>T (p.H309Y) alteration is located in exon 9 (coding exon 9) of the ANKRD13A gene. This alteration results from a C to T substitution at nucleotide position 925, causing the histidine (H) at amino acid position 309 to be replaced by a tyrosine (Y). 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	0.16
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.028	D
Polyphen		0.97	D
Vest4		0.50
MutPred		0.39		Gain of catalytic residue at Q314 (P = 2e-04);
MVP		0.60
MPC		0.93
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.43
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1313812596; hg19: chr12-110465551;