chr16-4698051-G-C

Position:

• chr16-4698051-G-C

Variant summary

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

The NM_133450.4(ANKS3):​c.1736C>G​(p.Ala579Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANKS3 NM_133450.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.830

Genes affected

ANKS3 (HGNC:29422): (ankyrin repeat and sterile alpha motif domain containing 3) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANKS3 (HGNC:):

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
ANKS3	NM_133450.4	c.1736C>G	p.Ala579Gly	missense_variant	15/18	ENST00000304283.9	NP_597707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKS3	ENST00000304283.9	c.1736C>G	p.Ala579Gly	missense_variant	15/18	2	NM_133450.4	ENSP00000304586.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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 17, 2023

The c.1736C>G (p.A579G) alteration is located in exon 15 (coding exon 13) of the ANKS3 gene. This alteration results from a C to G substitution at nucleotide position 1736, causing the alanine (A) at amino acid position 579 to be replaced by a glycine (G). 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	0.087
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0097	T;T;T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.71	T;T;T;.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.071	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;.;.;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	.;.;N;N;.
REVEL	Benign	0.066
Sift	Uncertain	0.0010	.;.;D;D;.
Sift4G	Benign	0.063	T;T;T;T;T
Polyphen		0.0020	B;.;.;B;.
Vest4		0.36
MutPred		0.10		Loss of stability (P = 0.2036);.;.;Loss of stability (P = 0.2036);.;
MVP		0.25
MPC		0.022
ClinPred		0.12	T
GERP RS		0.74
Varity_R		0.11
gMVP		0.044

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-4748052;