chr19-53140666-C-T

Variant names:

• chr19-53140666-C-T
• rs150489253
• NM_032584.3:c.2162G>A

Variant summary

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

The NM_032584.3(ZNF347):​c.2162G>A​(p.Arg721His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,602,820 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ZNF347 NM_032584.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.89

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=0.027639002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF347	NM_032584.3	c.2162G>A	p.Arg721His	missense_variant	Exon 5 of 5	ENST00000334197.12	NP_115973.2
ZNF347	NM_001172674.2	c.2165G>A	p.Arg722His	missense_variant	Exon 5 of 5		NP_001166145.1
ZNF347	NM_001172675.2	c.2165G>A	p.Arg722His	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.2162G>A	p.Arg721His	missense_variant	Exon 5 of 5	1	NM_032584.3	ENSP00000334146.6
ZNF347	ENST00000452676.6	c.2165G>A	p.Arg722His	missense_variant	Exon 5 of 5	2		ENSP00000405218.2
ZNF347	ENST00000601469.2	c.2165G>A	p.Arg722His	missense_variant	Exon 5 of 5	2		ENSP00000471712.2
ZNF347	ENST00000601804.5	c.97+8015G>A		intron_variant	Intron 3 of 3	4		ENSP00000470590.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 32 AN: 142920 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.000445

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000352

Gnomad OTH AF: 0.000515

GnomAD3 exomes AF: 0.000217 AC: 54 AN: 248746 Hom.: 0 AF XY: 0.000223 AC XY: 30 AN XY: 134518

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000444

Gnomad SAS exome AF: 0.0000994

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000257 AC: 375 AN: 1459766 Hom.: 0 Cov.: 31 AF XY: 0.000238 AC XY: 173 AN XY: 726170

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000273 AC: 39 AN: 143054 Hom.: 1 Cov.: 33 AF XY: 0.000244 AC XY: 17 AN XY: 69564

Gnomad4 AFR AF: 0.000261

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000632

Gnomad4 SAS AF: 0.000445

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000352

Gnomad4 OTH AF: 0.000510

Alfa AF: 0.000194 Hom.: 0

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2165G>A (p.R722H) alteration is located in exon 5 (coding exon 4) of the ZNF347 gene. This alteration results from a G to A substitution at nucleotide position 2165, causing the arginine (R) at amino acid position 722 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.5
DANN	Uncertain	0.97
DEOGEN2	Benign	0.041	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.087	T;T;.
M_CAP	Benign	0.00082	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.024
Sift	Benign	0.073	T;T;.
Sift4G	Benign	0.48	T;T;T
Polyphen		0.035	B;.;.
Vest4		0.043
MVP		0.13
MPC		0.013
ClinPred		0.11	T
GERP RS		-5.2
Varity_R		0.022
gMVP		0.026

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: rs150489253; hg19: chr19-53643919; COSMIC: COSV100498114; COSMIC: COSV100498114;