19-56663703-C-T

Variant names:

• chr19-56663703-C-T
• rs917684351
• NM_001005850.3:c.1496G>A

Variant summary

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

The NM_001005850.3(ZNF835):​c.1496G>A​(p.Ser499Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF835 NM_001005850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 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=0.06255272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF835	NM_001005850.3	c.1496G>A	p.Ser499Asn	missense_variant	Exon 2 of 2	ENST00000537055.4	NP_001005850.2
ZNF835	XM_005259382.3	c.1496G>A	p.Ser499Asn	missense_variant	Exon 2 of 2		XP_005259439.1
ZNF835	XM_005259383.4	c.1496G>A	p.Ser499Asn	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.1496G>A	p.Ser499Asn	missense_variant	Exon 2 of 2	2	NM_001005850.3	ENSP00000444747.1
ZIM2-AS1	ENST00000650950.1	n.202-3574C>T		intron_variant	Intron 2 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1496G>A (p.S499N) alteration is located in exon 2 (coding exon 1) of the ZNF835 gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the serine (S) at amino acid position 499 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	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.91
DEOGEN2	Benign	0.00076	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.098	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.31	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.059
Sift	Benign	0.23	T
Sift4G	Uncertain	0.028	D
Vest4		0.092
MVP		0.076
ClinPred		0.096	T
GERP RS		-3.4
Varity_R		0.054
gMVP		0.010

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: rs917684351; hg19: chr19-57175071;