2-70979254-T-G

Position:

• chr2-70979254-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001115116.2(ANKRD53):​c.328T>G​(p.Tyr110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,613,722 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: ANKRD53 NM_001115116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.129

Genes affected

ANKRD53 (HGNC:25691): (ankyrin repeat domain 53) Involved in mitotic metaphase plate congression; regulation of microtubule cytoskeleton organization; and regulation of mitotic cytokinesis. Located in spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

LOC105374795 (HGNC:):

TEX261 (HGNC:30712): (testis expressed 261) Predicted to enable COPII receptor activity. Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Predicted to act upstream of or within positive regulation of apoptotic process. Predicted to be located in cytoplasm. Predicted to be integral component of membrane. Predicted to be active in COPII-coated ER to Golgi transport vesicle. Predicted to be integral component of Golgi membrane and integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11545968).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD53	NM_001115116.2	c.328T>G	p.Tyr110Asp	missense_variant	2/6	ENST00000360589.4
LOC105374795	XR_001739534.2	n.440-2946A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD53	ENST00000360589.4	c.328T>G	p.Tyr110Asp	missense_variant	2/6	2	NM_001115116.2	A2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000232 AC: 58 AN: 250418 Hom.: 1 AF XY: 0.000243 AC XY: 33 AN XY: 135692

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1461344 Hom.: 3 Cov.: 35 AF XY: 0.000243 AC XY: 177 AN XY: 726968

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74524

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000302 Hom.: 3

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

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

Sep 27, 2021

The c.328T>G (p.Y110D) alteration is located in exon 2 (coding exon 2) of the ANKRD53 gene. This alteration results from a T to G substitution at nucleotide position 328, causing the tyrosine (Y) at amino acid position 110 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	0.29
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.5	L;.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.77	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.052	T;T;T;T
Sift4G	Benign	0.38	T;T;D;T
Polyphen		0.97	D;B;.;P
Vest4		0.46
MVP		0.74
MPC		0.78
ClinPred		0.0057	T
GERP RS		1.8
Varity_R		0.087
gMVP		0.69

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: rs145335113; hg19: chr2-71206384;