chr19-55614592-C-T

Variant names:

• chr19-55614592-C-T
• rs1344653284
• NM_001195605.2:c.974C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195605.2(ZNF865):​c.974C>T​(p.Pro325Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P325A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ZNF865 NM_001195605.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.833

Genes affected

ZNF865 (HGNC:38705): (zinc finger protein 865) Predicted to enable DNA-binding transcription factor activity 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12915835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF865	NM_001195605.2	c.974C>T	p.Pro325Leu	missense_variant	Exon 2 of 2	ENST00000568956.2	NP_001182534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF865	ENST00000568956.2	c.974C>T	p.Pro325Leu	missense_variant	Exon 2 of 2	2	NM_001195605.2	ENSP00000457715.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367194 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 674330

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: 0.00

Gnomad4 NFE exome AF: 9.34e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.974C>T (p.P325L) alteration is located in exon 1 (coding exon 1) of the ZNF865 gene. This alteration results from a C to T substitution at nucleotide position 974, causing the proline (P) at amino acid position 325 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	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.76
DEOGEN2	Benign	0.0059	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.13	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.0	N
Sift	Benign	0.31	T
Sift4G	Uncertain	0.025	D
Vest4		0.13
MVP		0.58
GERP RS		2.6
Varity_R		0.053
gMVP		0.14

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: rs1344653284; hg19: chr19-56125958;