chr12-51889089-A-T

Variant names:

• chr12-51889089-A-T
• rs697636
• NM_182608.4:c.419A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182608.4(ANKRD33):​c.419A>T​(p.Tyr140Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,934 control chromosomes in the GnomAD database, including 93,587 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7398 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86189 hom.)
• Consequence: ANKRD33 NM_182608.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.284

Genes affected

ANKRD33 (HGNC:13788): (ankyrin repeat domain 33) Predicted to be involved in negative regulation of transcription by RNA polymerase II and negative regulation of transcription regulatory region DNA binding activity. Predicted to act upstream of or within skeletal muscle cell differentiation. Predicted to be located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014339983).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD33	NM_182608.4	c.419A>T	p.Tyr140Phe	missense_variant	Exon 3 of 5	ENST00000301190.11	NP_872414.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD33	ENST00000301190.11	c.419A>T	p.Tyr140Phe	missense_variant	Exon 3 of 5	2	NM_182608.4	ENSP00000301190.6

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44808 AN: 151966 Hom.: 7398 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.352 AC: 88546 AN: 251288 AF XY: 0.356

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.418

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.339 AC: 494841 AN: 1461850 Hom.: 86189 Cov.: 62 AF XY: 0.342 AC XY: 248557 AN XY: 727232

Gnomad4 AFR exome AF: 0.146 AC: 4889 AN: 33480

Gnomad4 AMR exome AF: 0.438 AC: 19565 AN: 44716

Gnomad4 ASJ exome AF: 0.320 AC: 8370 AN: 26134

Gnomad4 EAS exome AF: 0.460 AC: 18277 AN: 39700

Gnomad4 SAS exome AF: 0.418 AC: 36017 AN: 86254

Gnomad4 FIN exome AF: 0.369 AC: 19702 AN: 53416

Gnomad4 NFE exome AF: 0.329 AC: 365913 AN: 1111990

Gnomad4 Remaining exome AF: 0.337 AC: 20326 AN: 60392

GnomAD4 genome AF: 0.295 AC: 44814 AN: 152084 Hom.: 7398 Cov.: 32 AF XY: 0.303 AC XY: 22514 AN XY: 74354

Gnomad4 AFR AF: 0.147 AC: 0.147074 AN: 0.147074

Gnomad4 AMR AF: 0.374 AC: 0.374183 AN: 0.374183

Gnomad4 ASJ AF: 0.324 AC: 0.324293 AN: 0.324293

Gnomad4 EAS AF: 0.409 AC: 0.408563 AN: 0.408563

Gnomad4 SAS AF: 0.426 AC: 0.425903 AN: 0.425903

Gnomad4 FIN AF: 0.383 AC: 0.382842 AN: 0.382842

Gnomad4 NFE AF: 0.331 AC: 0.33119 AN: 0.33119

Gnomad4 OTH AF: 0.303 AC: 0.303318 AN: 0.303318

Alfa AF: 0.317 Hom.: 2585

Bravo AF: 0.285

TwinsUK AF: 0.321 AC: 1192

ALSPAC AF: 0.330 AC: 1273

ESP6500AA AF: 0.144 AC: 634

ESP6500EA AF: 0.326 AC: 2800

ExAC AF: 0.344 AC: 41759

Asia WGS AF: 0.383 AC: 1332 AN: 3478

EpiCase AF: 0.333

EpiControl AF: 0.328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.91
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.072
Sift	Benign	0.15	T;T
Sift4G	Benign	0.088	T;T
Vest4		0.11
MPC		0.53
ClinPred		0.015	T
GERP RS		1.5
Varity_R		0.20
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs697636; hg19: chr12-52282873; COSMIC: COSV56608742; COSMIC: COSV56608742;