12-110012096-A-G

Variant names:

• chr12-110012096-A-G
• rs1357206361
• NM_033121.2:c.188A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033121.2(ANKRD13A):​c.188A>G​(p.His63Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,936 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD13A NM_033121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033121.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD13A	NM_033121.2	MANE Select	c.188A>G	p.His63Arg	missense	Exon 2 of 15	NP_149112.1	Q8IZ07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD13A	ENST00000261739.9	TSL:1 MANE Select	c.188A>G	p.His63Arg	missense	Exon 2 of 15	ENSP00000261739.4	Q8IZ07
	ANKRD13A	ENST00000550404.1	TSL:1	n.447A>G		non_coding_transcript_exon	Exon 2 of 7
	ANKRD13A	ENST00000553025.5	TSL:1	n.-77A>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000474172.1	S4R3D2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251440 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460936 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726652

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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111226

Other (OTH) AF: 0.00 AC: 0 AN: 60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.66	N
PhyloP100		8.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.48
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.48		Gain of MoRF binding (P = 0.0376)
MVP		0.71
MPC		1.0
ClinPred		0.92	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.56
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs1357206361; hg19: chr12-110449901; COSMIC: COSV99924037;