18-9254628-T-C

Variant names:

• chr18-9254628-T-C
• rs150317182
• NM_015208.5:c.1361T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015208.5(ANKRD12):​c.1361T>C​(p.Met454Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,581,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: ANKRD12 NM_015208.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.163

Genes affected

ANKRD12 (HGNC:29135): (ankyrin repeat domain 12) This gene encodes a member of the ankyrin repeats-containing cofactor family. These proteins may inhibit the transcriptional activity of nuclear receptors through the recruitment of histone deacetylases. The encoded protein interacts with p160 coactivators and also represses transcription mediated by the coactivator alteration/deficiency in activation 3 (ADA3). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008126706).
• BP6: Variant 18-9254628-T-C is Benign according to our data. Variant chr18-9254628-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3866567.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD12	NM_015208.5	c.1361T>C	p.Met454Thr	missense_variant	Exon 9 of 13	ENST00000262126.9	NP_056023.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD12	ENST00000262126.9	c.1361T>C	p.Met454Thr	missense_variant	Exon 9 of 13	1	NM_015208.5	ENSP00000262126.3
ANKRD12	ENST00000400020.7	c.1292T>C	p.Met431Thr	missense_variant	Exon 8 of 12	1		ENSP00000382897.3
ANKRD12	ENST00000359158.7	n.*475T>C		non_coding_transcript_exon_variant	Exon 4 of 4	2		ENSP00000352073.7
ANKRD12	ENST00000359158.7	n.*475T>C		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000352073.7

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151798 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000241 AC: 55 AN: 228406 Hom.: 1 AF XY: 0.000242 AC XY: 30 AN XY: 124096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.000333

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000352

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000549

GnomAD4 exome AF: 0.000173 AC: 248 AN: 1429548 Hom.: 1 Cov.: 32 AF XY: 0.000190 AC XY: 135 AN XY: 709688

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.000241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000319

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000356

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151916 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74226

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000950

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 21, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.065
DANN	Benign	0.68
DEOGEN2	Benign	0.0048	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.069	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.018
MVP		0.082
ClinPred		0.012	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.025

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: rs150317182; hg19: chr18-9254626;