19-51581419-T-C

Position:

• chr19-51581419-T-C

Variant summary

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

The NM_007147.4(ZNF175):​c.101T>C​(p.Val34Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF175 NM_007147.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF175	NM_007147.4	c.101T>C	p.Val34Ala	missense_variant	3/5	ENST00000262259.7	NP_009078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF175	ENST00000262259.7	c.101T>C	p.Val34Ala	missense_variant	3/5	1	NM_007147.4	ENSP00000262259.2
ZNF175	ENST00000436511.2	c.101T>C	p.Val34Ala	missense_variant	2/4	2		ENSP00000440578.1
ZNF175	ENST00000596504.1	c.101T>C	p.Val34Ala	missense_variant	3/3	2		ENSP00000470922.1
ZNF175	ENST00000600460.1	n.52T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000378

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

Dec 09, 2024

The c.101T>C (p.V34A) alteration is located in exon 3 (coding exon 2) of the ZNF175 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the valine (V) at amino acid position 34 to be replaced by an alanine (A). 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	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.064	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.013	B;.;.
Vest4		0.47
MutPred		0.77		Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);
MVP		0.37
MPC		0.16
ClinPred		0.36	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.13

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: rs1445236073; hg19: chr19-52084672;