chr15-64499540-G-A

Position:

• chr15-64499540-G-A

Variant summary

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

The NM_015042.2(ZNF609):​c.121G>A​(p.Asp41Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF609 NM_015042.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

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.121G>A	p.Asp41Asn	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.121G>A	p.Asp41Asn	missense_variant	2/10	5	NM_015042.2	ENSP00000316527.3
ZNF609	ENST00000416172.1	c.121G>A	p.Asp41Asn	missense_variant	2/2	2		ENSP00000388846.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 30, 2022

The c.121G>A (p.D41N) alteration is located in exon 1 (coding exon 1) of the ZNF609 gene. This alteration results from a G to A substitution at nucleotide position 121, causing the aspartic acid (D) at amino acid position 41 to be replaced by an asparagine (N). 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	1.0
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.079	T;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.44		Loss of stability (P = 0.1226);Loss of stability (P = 0.1226);
MVP		0.79
MPC		0.93
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.80

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: rs750522477; hg19: chr15-64791739; COSMIC: COSV58581432; COSMIC: COSV58581432;