4-85781-G-T

Position:

• chr4-85781-G-T

Variant summary

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

The NM_182524.4(ZNF595):​c.277G>T​(p.Asp93Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF595 NM_182524.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

Genes affected

ZNF595 (HGNC:27196): (zinc finger protein 595) This gene encodes a protein belonging to the Cys2His2 zinc finger protein family, whose members function as transcription factors that can regulate a broad variety of developmental and cellular processes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Oct 2013]

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=0.19095531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF595	NM_182524.4	c.277G>T	p.Asp93Tyr	missense_variant	4/4	ENST00000610261.6	NP_872330.1
ZNF595	NM_001286052.2	c.181G>T	p.Asp61Tyr	missense_variant	3/3		NP_001272981.1
ZNF595	NM_001286053.2	c.-273G>T		5_prime_UTR_variant	2/2		NP_001272982.1
ZNF595	NM_001286054.2	c.-273G>T		5_prime_UTR_variant	5/5		NP_001272983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF595	ENST00000610261.6	c.277G>T	p.Asp93Tyr	missense_variant	4/4	1	NM_182524.4	ENSP00000477392.1
ZNF595	ENST00000609518.5	c.181G>T	p.Asp61Tyr	missense_variant	3/3	2		ENSP00000476408.2
ZNF595	ENST00000608255	c.-273G>T		5_prime_UTR_variant	2/2	2		ENSP00000476367.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460080 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

May 15, 2024

The c.277G>T (p.D93Y) alteration is located in exon 4 (coding exon 4) of the ZNF595 gene. This alteration results from a G to T substitution at nucleotide position 277, causing the aspartic acid (D) at amino acid position 93 to be replaced by a tyrosine (Y). 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	0.077
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.10	T;.
FATHMM_MKL	Benign	0.00018	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.19	T;T
Sift4G	Uncertain	0.040	D;D
Polyphen		0.39	B;.
Vest4		0.29
MVP		0.31
GERP RS		-2.2
Varity_R		0.043
gMVP		0.085

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: rs1714110255; hg19: chr4-85672;