1-1419512-C-T

Position:

• chr1-1419512-C-T

Variant summary

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

The NM_001145210.3(ANKRD65):​c.788G>A​(p.Gly263Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,388,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 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: 0.0000022 (0 hom.)
• Consequence: ANKRD65 NM_001145210.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.705

Genes affected

ANKRD65 (HGNC:42950): (ankyrin repeat domain 65)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04468292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD65	NM_001145210.3	c.788G>A	p.Gly263Asp	missense_variant	4/4	ENST00000537107.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD65	ENST00000537107.6	c.788G>A	p.Gly263Asp	missense_variant	4/4	5	NM_001145210.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1388874 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685150

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000245

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Mar 27, 2023

The c.788G>A (p.G263D) alteration is located in exon 4 (coding exon 3) of the ANKRD65 gene. This alteration results from a G to A substitution at nucleotide position 788, causing the glycine (G) at amino acid position 263 to be replaced by an aspartic acid (D). 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	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.56
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.28	T;T
Vest4		0.23
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);
MVP		0.030
ClinPred		0.018	T
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1645506091; hg19: chr1-1354892;