8-12112832-A-G

Variant names:

• chr8-12112832-A-G
• rs1177960662
• NM_001039615.3:c.577A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001039615.3(ZNF705D):​c.577A>G​(p.Thr193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 4)
  • Exomes 𝑓: 0.00011 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF705D NM_001039615.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086450845).

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.577A>G	p.Thr193Ala	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.577A>G	p.Thr193Ala	missense	Exon 7 of 7	ENSP00000382957.3	P0CH99

Frequencies

GnomAD3 genomes AF: 0.000574 AC: 16 AN: 27854 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000695

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000109 AC: 55 AN: 504360 Hom.: 2 Cov.: 6 AF XY: 0.000105 AC XY: 27 AN XY: 258260

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

African (AFR) AF: 0.00129 AC: 22 AN: 17064

American (AMR) AF: 0.00 AC: 0 AN: 13884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11966

East Asian (EAS) AF: 0.000733 AC: 17 AN: 23184

South Asian (SAS) AF: 0.000110 AC: 4 AN: 36474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1814

European-Non Finnish (NFE) AF: 0.00000855 AC: 3 AN: 350710

Other (OTH) AF: 0.000352 AC: 9 AN: 25552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000573 AC: 16 AN: 27904 Hom.: 0 Cov.: 4 AF XY: 0.000795 AC XY: 10 AN XY: 12576

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

African (AFR) AF: 0.00132 AC: 15 AN: 11370

American (AMR) AF: 0.000695 AC: 1 AN: 1438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 592

East Asian (EAS) AF: 0.00 AC: 0 AN: 332

South Asian (SAS) AF: 0.00 AC: 0 AN: 396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12008

Other (OTH) AF: 0.00 AC: 0 AN: 270

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000422 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	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.055
Sift	Benign	0.35	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.52		Loss of stability (P = 0.0891)
MVP		0.030
ClinPred		0.041	T
GERP RS		1.0
Varity_R		0.072
gMVP		0.0066
Mutation Taster		=91/9	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: rs1177960662; hg19: chr8-11970341; COSMIC: COSV67956444; COSMIC: COSV67956444;