rs375760699

Variant names:

• chr4-85997-A-G
• rs375760699
• NM_182524.4:c.493A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182524.4(ZNF595):​c.493A>G​(p.Ile165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,608,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ZNF595 NM_182524.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.35
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049398303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF595	NM_182524.4	c.493A>G	p.Ile165Val	missense_variant	Exon 4 of 4	ENST00000610261.6	NP_872330.1
ZNF595	NM_001286052.2	c.397A>G	p.Ile133Val	missense_variant	Exon 3 of 3		NP_001272981.1
ZNF595	NM_001286053.2	c.-57A>G		5_prime_UTR_variant	Exon 2 of 2		NP_001272982.1
ZNF595	NM_001286054.2	c.-57A>G		5_prime_UTR_variant	Exon 5 of 5		NP_001272983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF595	ENST00000610261.6	c.493A>G	p.Ile165Val	missense_variant	Exon 4 of 4	1	NM_182524.4	ENSP00000477392.1
ZNF595	ENST00000609518.5	c.397A>G	p.Ile133Val	missense_variant	Exon 3 of 3	2		ENSP00000476408.2
ZNF595	ENST00000608255.2	c.-57A>G		5_prime_UTR_variant	Exon 2 of 2	2		ENSP00000476367.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000850 AC: 20 AN: 235266 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000687

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000270 AC: 393 AN: 1455774 Hom.: 0 Cov.: 32 AF XY: 0.000246 AC XY: 178 AN XY: 723666

African (AFR) AF: 0.000210 AC: 7 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 43408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000342 AC: 379 AN: 1108552

Other (OTH) AF: 0.0000997 AC: 6 AN: 60190

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74364

African (AFR) AF: 0.0000965 AC: 4 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.0000413 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493A>G (p.I165V) alteration is located in exon 4 (coding exon 4) of the ZNF595 gene. This alteration results from a A to G substitution at nucleotide position 493, causing the isoleucine (I) at amino acid position 165 to be replaced by a valine (V). 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	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.6
DANN	Benign	0.90
DEOGEN2	Benign	0.011	T;.
FATHMM_MKL	Benign	0.00057	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.049	T;T
PhyloP100		-3.4
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;.
Vest4		0.019
MVP		0.16
GERP RS		1.1
Varity_R		0.031
gMVP		0.0027

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375760699; hg19: chr4-85888;