10-37145055-G-T

Position:

• chr10-37145055-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_052997.3(ANKRD30A):​c.1454G>T​(p.Arg485Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,391,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.032 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0037 (0 hom.)
• Consequence: ANKRD30A NM_052997.3 missense, splice_region
• Scores: Splicing: ADA: 0.001864
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.593

Genes affected

ANKRD30A (HGNC:17234): (ankyrin repeat domain 30A) This gene encodes a DNA-binding transcription factor that is uniquely expressed in mammary epithelium and the testis. Altered expression levels have been associated with breast cancer progression. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006854266).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.032 (2789/87222) while in subpopulation SAS AF= 0.041 (110/2682). AF 95% confidence interval is 0.0348. There are 0 homozygotes in gnomad4. There are 1440 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD30A	NM_052997.3	c.1454G>T	p.Arg485Leu	missense_variant, splice_region_variant	8/36	ENST00000361713.2	NP_443723.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD30A	ENST00000361713.2	c.1454G>T	p.Arg485Leu	missense_variant, splice_region_variant	8/36	5	NM_052997.3	ENSP00000354432	A2
ANKRD30A	ENST00000374660.7	c.1454G>T	p.Arg485Leu	missense_variant, splice_region_variant	8/42	5		ENSP00000363792	P4
ANKRD30A	ENST00000602533.7	c.1454G>T	p.Arg485Leu	missense_variant, splice_region_variant	8/36	5		ENSP00000473551	A2

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 2786 AN: 87148 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00183

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0221

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.0104

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0347

GnomAD3 exomes AF: 0.000184 AC: 43 AN: 233064 Hom.: 0 AF XY: 0.000173 AC XY: 22 AN XY: 126942

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.0000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.00367 AC: 4791 AN: 1304536 Hom.: 0 Cov.: 27 AF XY: 0.00376 AC XY: 2420 AN XY: 644304

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.00274

Gnomad4 EAS exome AF: 0.00281

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.0320 AC: 2789 AN: 87222 Hom.: 0 Cov.: 34 AF XY: 0.0339 AC XY: 1440 AN XY: 42478

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.0379

Gnomad4 ASJ AF: 0.0221

Gnomad4 EAS AF: 0.0183

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.0428

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0342

Alfa AF: 0.00221 Hom.: 0

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000215 AC: 26

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

Jul 15, 2021

The c.1286G>T (p.R429L) alteration is located in exon 8 (coding exon 8) of the ANKRD30A gene. This alteration results from a G to T substitution at nucleotide position 1286, causing the arginine (R) at amino acid position 429 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.1
DANN	Benign	0.94
DEOGEN2	Benign	0.0016	T;T;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.36	T;T;T;.
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.73	.;N;N;.
REVEL	Benign	0.0090
Sift	Benign	0.16	.;T;T;.
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.19	B;.;.;.
Vest4		0.11
MVP		0.39
MPC		0.011
ClinPred		0.034	T
GERP RS		-0.12
Varity_R		0.056
gMVP		0.0017

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.15		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: rs200164455; hg19: chr10-37433983; COSMIC: COSV64604221;