NM_001039615.3:c.652C>T

Variant names:

• chr8-12112907-C-T
• rs1436692718
• NM_001039615.3:c.652C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001039615.3(ZNF705D):​c.652C>T​(p.His218Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 6)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF705D NM_001039615.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98
• Publications: 0 publications found

Genes affected

ZNF705D (HGNC:33202): (zinc finger protein 705D) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039615.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF705D	NM_001039615.3	MANE Select	c.652C>T	p.His218Tyr	missense	Exon 7 of 7	NP_001034704.2	P0CH99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF705D	ENST00000400085.8	TSL:5 MANE Select	c.652C>T	p.His218Tyr	missense	Exon 7 of 7	ENSP00000382957.3	P0CH99

Frequencies

GnomAD3 genomes AF: 0.0000391 AC: 2 AN: 51126 Hom.: 0 Cov.: 6

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: 0.0000860

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000104 AC: 9 AN: 863484 Hom.: 0 Cov.: 12 AF XY: 0.00000916 AC XY: 4 AN XY: 436618

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

African (AFR) AF: 0.00 AC: 0 AN: 25996

American (AMR) AF: 0.00 AC: 0 AN: 22744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17146

East Asian (EAS) AF: 0.00 AC: 0 AN: 29042

South Asian (SAS) AF: 0.00 AC: 0 AN: 55950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2588

European-Non Finnish (NFE) AF: 0.0000126 AC: 8 AN: 635102

Other (OTH) AF: 0.0000261 AC: 1 AN: 38344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000467562), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000391 AC: 2 AN: 51126 Hom.: 0 Cov.: 6 AF XY: 0.0000425 AC XY: 1 AN XY: 23554

⚠️ 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: 19196

American (AMR) AF: 0.00 AC: 0 AN: 2966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1136

East Asian (EAS) AF: 0.00 AC: 0 AN: 884

South Asian (SAS) AF: 0.00 AC: 0 AN: 726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.0000860 AC: 2 AN: 23258

Other (OTH) AF: 0.00 AC: 0 AN: 508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0042	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.89		Loss of disorder (P = 0.0325)
MVP		0.60
ClinPred		0.99	D
GERP RS		1.0
Varity_R		0.54
gMVP		0.082
Mutation Taster		=93/7	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: rs1436692718; hg19: chr8-11970416;