NM_144698.5:c.2059A>G

Variant names:

• chr1-145872710-T-C
• rs1653886234
• NM_144698.5:c.2059A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144698.5(ANKRD35):​c.2059A>G​(p.Thr687Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ANKRD35 NM_144698.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.150

Genes affected

ANKRD35 (HGNC:26323): (ankyrin repeat domain 35)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12879622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD35	NM_144698.5	c.2059A>G	p.Thr687Ala	missense_variant	Exon 10 of 14	ENST00000355594.9	NP_653299.4
ANKRD35	NM_001280799.2	c.1789A>G	p.Thr597Ala	missense_variant	Exon 8 of 12		NP_001267728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD35	ENST00000355594.9	c.2059A>G	p.Thr687Ala	missense_variant	Exon 10 of 14	2	NM_144698.5	ENSP00000347802.4
ANKRD35	ENST00000544626.2	c.1789A>G	p.Thr597Ala	missense_variant	Exon 8 of 12	5		ENSP00000442671.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461826 Hom.: 0 Cov.: 96 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2059A>G (p.T687A) alteration is located in exon 10 (coding exon 10) of the ANKRD35 gene. This alteration results from a A to G substitution at nucleotide position 2059, causing the threonine (T) at amino acid position 687 to be replaced by an alanine (A). 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	0.096
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.030	.;T
LIST_S2	Benign	0.54	.;T
MetaRNN	Benign	0.13	T;T
PROVEAN	Benign	-0.50	N;.
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.53	T;T
Vest4		0.16
gMVP		0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1653886234; hg19: chr1-145562371;