chr19-52154945-G-C

Variant names:

• chr19-52154945-G-C
• rs1460981835
• NM_001102657.3:c.2738C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102657.3(ZNF836):​c.2738C>G​(p.Thr913Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,580,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZNF836 NM_001102657.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.706
• Publications: 0 publications found

Genes affected

ZNF836 (HGNC:34333): (zinc finger protein 836) 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]

ENSG00000267827 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085371226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF836	NM_001102657.3	c.2738C>G	p.Thr913Ser	missense_variant	Exon 5 of 5	ENST00000682614.1	NP_001096127.1
ZNF836	XM_011526558.4	c.2738C>G	p.Thr913Ser	missense_variant	Exon 5 of 5		XP_011524860.1
ZNF836	XM_011526559.4	c.2738C>G	p.Thr913Ser	missense_variant	Exon 4 of 4		XP_011524861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF836	ENST00000682614.1	c.2738C>G	p.Thr913Ser	missense_variant	Exon 5 of 5		NM_001102657.3	ENSP00000507838.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428380 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707700

African (AFR) AF: 0.00 AC: 0 AN: 31980

American (AMR) AF: 0.00 AC: 0 AN: 38980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 80754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096196

Other (OTH) AF: 0.00 AC: 0 AN: 58894

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2738C>G (p.T913S) alteration is located in exon 5 (coding exon 3) of the ZNF836 gene. This alteration results from a C to G substitution at nucleotide position 2738, causing the threonine (T) at amino acid position 913 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	0.096
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.98
DANN	Benign	0.84
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.0055	T;T
M_CAP	Benign	0.00077	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.71
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.0070
Sift	Benign	0.051	.;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0050	B;.
Vest4		0.024
MutPred		0.24		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.067
MPC		0.12
ClinPred		0.024	T
GERP RS		-3.2
Varity_R		0.062
gMVP		0.0068
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1460981835; hg19: chr19-52658198;