19-51587007-G-T

Position:

• chr19-51587007-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000262259.7(ZNF175):​c.676G>T​(p.Val226Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V226I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF175 ENST00000262259.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.353

Genes affected

ZNF175 (HGNC:12964): (zinc finger protein 175) Enables DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II and positive regulation of transcription by RNA polymerase II. Located in cytosol; intermediate filament cytoskeleton; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07073158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF175	NM_007147.4	c.676G>T	p.Val226Phe	missense_variant	5/5	ENST00000262259.7	NP_009078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF175	ENST00000262259.7	c.676G>T	p.Val226Phe	missense_variant	5/5	1	NM_007147.4	ENSP00000262259	P1
ZNF175	ENST00000436511.2	c.296-2541G>T		intron_variant		2		ENSP00000440578
ZNF175	ENST00000600460.1	n.627G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.676G>T (p.V226F) alteration is located in exon 5 (coding exon 4) of the ZNF175 gene. This alteration results from a G to T substitution at nucleotide position 676, causing the valine (V) at amino acid position 226 to be replaced by a phenylalanine (F). 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	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.25
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00061	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.014
Sift	Benign	0.39	T
Sift4G	Benign	0.67	T
Polyphen		0.21	B
Vest4		0.14
MutPred		0.55		Gain of catalytic residue at V226 (P = 0.0153);
MVP		0.072
MPC		0.17
ClinPred		0.093	T
GERP RS		-2.7
Varity_R		0.028
gMVP		0.036

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: rs372054272; hg19: chr19-52090260;