19-53140931-C-A

Variant names:

• chr19-53140931-C-A
• rs751920286
• NM_032584.3:c.1897G>T

Variant summary

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

The NM_032584.3(ZNF347):​c.1897G>T​(p.Ala633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,222 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ZNF347 NM_032584.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29

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=0.059523135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF347	NM_032584.3	c.1897G>T	p.Ala633Ser	missense_variant	Exon 5 of 5	ENST00000334197.12	NP_115973.2
ZNF347	NM_001172674.2	c.1900G>T	p.Ala634Ser	missense_variant	Exon 5 of 5		NP_001166145.1
ZNF347	NM_001172675.2	c.1900G>T	p.Ala634Ser	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.1897G>T	p.Ala633Ser	missense_variant	Exon 5 of 5	1	NM_032584.3	ENSP00000334146.6
ZNF347	ENST00000452676.6	c.1900G>T	p.Ala634Ser	missense_variant	Exon 5 of 5	2		ENSP00000405218.2
ZNF347	ENST00000601469.2	c.1900G>T	p.Ala634Ser	missense_variant	Exon 5 of 5	2		ENSP00000471712.2
ZNF347	ENST00000601804.5	c.97+7750G>T		intron_variant	Intron 3 of 3	4		ENSP00000470590.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151452 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251212 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151452 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73892

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1900G>T (p.A634S) alteration is located in exon 5 (coding exon 4) of the ZNF347 gene. This alteration results from a G to T substitution at nucleotide position 1900, causing the alanine (A) at amino acid position 634 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.12	T;T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Benign	0.067
Sift	Uncertain	0.024	D;D;.
Sift4G	Benign	0.064	T;D;D
Polyphen		0.44	B;.;.
Vest4		0.12
MutPred		0.34		Gain of disorder (P = 0.0318);.;.;
MVP		0.13
MPC		0.027
ClinPred		0.11	T
GERP RS		-2.3
Varity_R		0.072
gMVP		0.035

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: rs751920286; hg19: chr19-53644184;