chr20-45948675-C-T

Variant names:

• chr20-45948675-C-T
• rs3363
• NM_022095.4:c.*278G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022095.4(ZNF335):​c.*278G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 448,752 control chromosomes in the GnomAD database, including 5,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2514 hom., cov: 33)
  • Exomes 𝑓: 0.14 (3474 hom.)
• Consequence: ZNF335 NM_022095.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.441
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 20-45948675-C-T is Benign according to our data. Variant chr20-45948675-C-T is described in ClinVar as [Benign]. Clinvar id is 1231704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF335	NM_022095.4	c.*278G>A		3_prime_UTR_variant	Exon 28 of 28	ENST00000322927.3	NP_071378.1
ZNF335	XM_047440363.1	c.*278G>A		3_prime_UTR_variant	Exon 27 of 27		XP_047296319.1
ZNF335	XM_005260504.5	c.*278G>A		3_prime_UTR_variant	Exon 27 of 27		XP_005260561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF335	ENST00000322927.3	c.*278G>A		3_prime_UTR_variant	Exon 28 of 28	1	NM_022095.4	ENSP00000325326.2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25179 AN: 152042 Hom.: 2511 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0961

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.137 AC: 40618 AN: 296590 Hom.: 3474 Cov.: 3 AF XY: 0.140 AC XY: 22109 AN XY: 157834

African (AFR) AF: 0.265 AC: 2267 AN: 8554

American (AMR) AF: 0.0944 AC: 1317 AN: 13948

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 901 AN: 8484

East Asian (EAS) AF: 0.315 AC: 5211 AN: 16548

South Asian (SAS) AF: 0.176 AC: 7496 AN: 42628

European-Finnish (FIN) AF: 0.111 AC: 1765 AN: 15894

Middle Eastern (MID) AF: 0.100 AC: 122 AN: 1216

European-Non Finnish (NFE) AF: 0.112 AC: 19433 AN: 172944

Other (OTH) AF: 0.129 AC: 2106 AN: 16374

GnomAD4 genome AF: 0.166 AC: 25202 AN: 152162 Hom.: 2514 Cov.: 33 AF XY: 0.167 AC XY: 12409 AN XY: 74366

African (AFR) AF: 0.273 AC: 11321 AN: 41504

American (AMR) AF: 0.0962 AC: 1472 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3472

East Asian (EAS) AF: 0.325 AC: 1670 AN: 5146

South Asian (SAS) AF: 0.187 AC: 904 AN: 4830

European-Finnish (FIN) AF: 0.125 AC: 1321 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7725 AN: 67992

Other (OTH) AF: 0.139 AC: 294 AN: 2110

Alfa AF: 0.129 Hom.: 4047

Bravo AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs3363; hg19: chr20-44577314;