15-64499481-A-G

Position:

• chr15-64499481-A-G

Variant summary

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

The NM_015042.2(ZNF609):​c.62A>G​(p.Tyr21Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZNF609 NM_015042.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23

Genes affected

ZNF609 (HGNC:29003): (zinc finger protein 609) Predicted to enable promoter-specific chromatin binding activity. Involved in regulation of myoblast proliferation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF609	NM_015042.2	c.62A>G	p.Tyr21Cys	missense_variant	2/10	ENST00000326648.5	NP_055857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF609	ENST00000326648.5	c.62A>G	p.Tyr21Cys	missense_variant	2/10	5	NM_015042.2	ENSP00000316527.3
ZNF609	ENST00000416172.1	c.62A>G	p.Tyr21Cys	missense_variant	2/2	2		ENSP00000388846.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

Jan 31, 2022

The c.62A>G (p.Y21C) alteration is located in exon 1 (coding exon 1) of the ZNF609 gene. This alteration results from a A to G substitution at nucleotide position 62, causing the tyrosine (Y) at amino acid position 21 to be replaced by a cysteine (C). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.51		Loss of phosphorylation at Y21 (P = 0.0346);Loss of phosphorylation at Y21 (P = 0.0346);
MVP		0.22
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.26

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: rs1893528224; hg19: chr15-64791680;