19-53140463-C-T

Variant names:

• chr19-53140463-C-T
• rs369373570
• NM_032584.3:c.2365G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_032584.3(ZNF347):​c.2365G>A​(p.Gly789Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,613,764 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (1 hom.)
• Consequence: ZNF347 NM_032584.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282

Genes affected

ZNF347 (HGNC:16447): (zinc finger protein 347) Predicted to enable DNA-binding transcription factor 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]

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=0.09794161).
• BP6: Variant 19-53140463-C-T is Benign according to our data. Variant chr19-53140463-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2397417.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF347	NM_032584.3	c.2365G>A	p.Gly789Arg	missense_variant	Exon 5 of 5	ENST00000334197.12	NP_115973.2
ZNF347	NM_001172674.2	c.2368G>A	p.Gly790Arg	missense_variant	Exon 5 of 5		NP_001166145.1
ZNF347	NM_001172675.2	c.2368G>A	p.Gly790Arg	missense_variant	Exon 5 of 5		NP_001166146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF347	ENST00000334197.12	c.2365G>A	p.Gly789Arg	missense_variant	Exon 5 of 5	1	NM_032584.3	ENSP00000334146.6
ZNF347	ENST00000452676.6	c.2368G>A	p.Gly790Arg	missense_variant	Exon 5 of 5	2		ENSP00000405218.2
ZNF347	ENST00000601469.2	c.2368G>A	p.Gly790Arg	missense_variant	Exon 5 of 5	2		ENSP00000471712.2
ZNF347	ENST00000601804.5	c.97+8218G>A		intron_variant	Intron 3 of 3	4		ENSP00000470590.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251206 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461722 Hom.: 1 Cov.: 30 AF XY: 0.0000770 AC XY: 56 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74260

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 10, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.031	T;T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Benign	0.055
Sift	Benign	0.037	D;D;.
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.13
MutPred		0.32		Gain of MoRF binding (P = 0.0181);.;.;
MVP		0.095
MPC		0.044
ClinPred		0.37	T
GERP RS		-4.9
Varity_R		0.15
gMVP		0.0081

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: rs369373570; hg19: chr19-53643716; COSMIC: COSV100498331; COSMIC: COSV100498331;