NM_022095.4:c.1963C>T

Variant names:

• chr20-45960265-G-A
• rs117132825
• NM_022095.4:c.1963C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022095.4(ZNF335):​c.1963C>T​(p.Pro655Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,152 control chromosomes in the GnomAD database, including 259 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0076 (16 hom., cov: 32)
  • Exomes 𝑓: 0.012 (243 hom.)
• Consequence: ZNF335 NM_022095.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.93
• Publications: 12 publications found

Genes affected

ZNF335 (HGNC:15807): (zinc finger protein 335) The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]

ZNF335 Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism due to ZNF335 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005218357).
• BP6: Variant 20-45960265-G-A is Benign according to our data. Variant chr20-45960265-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212643.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0076 (1158/152282) while in subpopulation SAS AF = 0.0447 (216/4828). AF 95% confidence interval is 0.0399. There are 16 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022095.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	NM_022095.4	MANE Select	c.1963C>T	p.Pro655Ser	missense	Exon 14 of 28	NP_071378.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	ENST00000322927.3	TSL:1 MANE Select	c.1963C>T	p.Pro655Ser	missense	Exon 14 of 28	ENSP00000325326.2
	ZNF335	ENST00000944756.1		c.1963C>T	p.Pro655Ser	missense	Exon 14 of 28	ENSP00000614815.1
	ZNF335	ENST00000862676.1		c.1960C>T	p.Pro654Ser	missense	Exon 13 of 27	ENSP00000532735.1

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1161 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0117 AC: 2944 AN: 251418 AF XY: 0.0139

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0124 AC: 18177 AN: 1461870 Hom.: 243 Cov.: 33 AF XY: 0.0136 AC XY: 9875 AN XY: 727238

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00537 AC: 240 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0454 AC: 3918 AN: 86248

European-Finnish (FIN) AF: 0.00326 AC: 174 AN: 53420

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12893 AN: 1112002

Other (OTH) AF: 0.0125 AC: 752 AN: 60396

GnomAD4 genome AF: 0.00760 AC: 1158 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00783 AC XY: 583 AN XY: 74452

African (AFR) AF: 0.00209 AC: 87 AN: 41556

American (AMR) AF: 0.00758 AC: 116 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0447 AC: 216 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 691 AN: 68008

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00954 Hom.: 33

Bravo AF: 0.00622

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.0120 AC: 1452

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0109

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	not specified (1)
-	-	1	ZNF335-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.47	T
Polyphen		0.92	P
Vest4		0.14
MPC		0.36
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.024
gMVP		0.44
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117132825; hg19: chr20-44588904; COSMIC: COSV99071815; COSMIC: COSV99071815;