19-56664276-C-A

Variant names:

• chr19-56664276-C-A
• rs762463668
• NM_001005850.3:c.923G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001005850.3(ZNF835):​c.923G>T​(p.Cys308Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: ZNF835 NM_001005850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

ZNF835 (HGNC:34332): (zinc finger protein 835) 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]

ZIM2-AS1 (HGNC:51304): (ZIM2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF835	NM_001005850.3	c.923G>T	p.Cys308Phe	missense_variant	Exon 2 of 2	ENST00000537055.4	NP_001005850.2
ZNF835	XM_005259382.3	c.923G>T	p.Cys308Phe	missense_variant	Exon 2 of 2		XP_005259439.1
ZNF835	XM_005259383.4	c.923G>T	p.Cys308Phe	missense_variant	Exon 2 of 2		XP_005259440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF835	ENST00000537055.4	c.923G>T	p.Cys308Phe	missense_variant	Exon 2 of 2	2	NM_001005850.3	ENSP00000444747.1
ZIM2-AS1	ENST00000650950.1	n.202-3001C>A		intron_variant	Intron 2 of 5

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.923G>T (p.C308F) alteration is located in exon 2 (coding exon 1) of the ZNF835 gene. This alteration results from a G to T substitution at nucleotide position 923, causing the cysteine (C) at amino acid position 308 to be replaced by a phenylalanine (F). 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	0.82
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.54
MVP		0.51
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.86
gMVP		0.12

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: rs762463668; hg19: chr19-57175644;