NM_013275.6:c.7963A>G

Variant names:

• chr16-89268507-T-C
• rs1478078308
• NM_013275.6:c.7963A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_013275.6(ANKRD11):​c.7963A>G​(p.Asn2655Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

Genes affected

ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]

ENSG00000268218 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Important for protein degradation (size 294) in uniprot entity ANR11_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_013275.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.7963A>G	p.Asn2655Asp	missense_variant	Exon 13 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.7963A>G	p.Asn2655Asp	missense_variant	Exon 14 of 14		NP_001243111.1
ANKRD11	NM_001256183.2	c.7963A>G	p.Asn2655Asp	missense_variant	Exon 13 of 13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7963A>G	p.Asn2655Asp	missense_variant	Exon 13 of 13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.72	D;D;.;D
Eigen	Benign	0.062
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;D;D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.014	D;D;.;.
Polyphen		0.65	P;P;.;P
Vest4		0.76
MutPred		0.33		Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);
MVP		0.55
MPC		3.2
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.54
gMVP		0.94

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: rs1478078308; hg19: chr16-89334915;