chr19-22757978-G-C

Position:

• chr19-22757978-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080409.3(ZNF99):​c.1931C>G​(p.Thr644Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF99 NM_001080409.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.336

Genes affected

ZNF99 (HGNC:13175): (zinc finger protein 99) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053081155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF99	NM_001080409.3	c.1931C>G	p.Thr644Ser	missense_variant	4/4	ENST00000596209.4	NP_001073878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF99	ENST00000596209.4	c.1931C>G	p.Thr644Ser	missense_variant	4/4	5	NM_001080409.3	ENSP00000472969.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 32

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

Jun 14, 2024

The c.1931C>G (p.T644S) alteration is located in exon 4 (coding exon 4) of the ZNF99 gene. This alteration results from a C to G substitution at nucleotide position 1931, causing the threonine (T) at amino acid position 644 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.2
DANN	Benign	0.42
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.0069	T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	0.76	N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Benign	0.056
Sift	Benign	0.070	.;T
Sift4G	Benign	0.10	T;T
Vest4		0.072
MVP		0.014
MPC		0.016
ClinPred		0.22	T
GERP RS		-0.17
Varity_R		0.035
gMVP		0.0054

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-22940780; COSMIC: COSV68056762;