rs2228276

Variant names:

• chr19-58068272-C-T
• rs2228276
• NM_001289401.2:c.1788C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_001289401.2(ZNF135):​c.1788C>T​(p.His596His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,644 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (22 hom.)
• Consequence: ZNF135 NM_001289401.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.51
• Publications: 4 publications found

Genes affected

ZNF135 (HGNC:12919): (zinc finger protein 135) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in cytoskeleton organization and regulation of cell morphogenesis. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 19-58068272-C-T is Benign according to our data. Variant chr19-58068272-C-T is described in ClinVar as Benign. ClinVar VariationId is 781539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1648/151750) while in subpopulation AFR AF = 0.0365 (1509/41344). AF 95% confidence interval is 0.035. There are 24 homozygotes in GnomAd4. There are 769 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289401.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF135	NM_001289401.2	MANE Select	c.1788C>T	p.His596His	synonymous	Exon 5 of 5	NP_001276330.1
	ZNF135	NM_007134.1		c.1860C>T	p.His620His	synonymous	Exon 4 of 4	NP_009065.1
	ZNF135	NM_003436.4		c.1824C>T	p.His608His	synonymous	Exon 5 of 5	NP_003427.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF135	ENST00000313434.10	TSL:1 MANE Select	c.1788C>T	p.His596His	synonymous	Exon 5 of 5	ENSP00000321406.5
	ZNF135	ENST00000401053.8	TSL:1	c.1860C>T	p.His620His	synonymous	Exon 4 of 4	ENSP00000441410.1
	ZNF135	ENST00000511556.5	TSL:2	c.1824C>T	p.His608His	synonymous	Exon 5 of 5	ENSP00000422074.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1646 AN: 151632 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00819

GnomAD2 exomes AF: 0.00360 AC: 905 AN: 251392 AF XY: 0.00286

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00147 AC: 2142 AN: 1461894 Hom.: 22 Cov.: 34 AF XY: 0.00127 AC XY: 922 AN XY: 727248

African (AFR) AF: 0.0343 AC: 1150 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 285 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000313 AC: 348 AN: 1112012

Other (OTH) AF: 0.00253 AC: 153 AN: 60396

GnomAD4 genome AF: 0.0109 AC: 1648 AN: 151750 Hom.: 24 Cov.: 33 AF XY: 0.0104 AC XY: 769 AN XY: 74170

African (AFR) AF: 0.0365 AC: 1509 AN: 41344

American (AMR) AF: 0.00406 AC: 62 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000295 AC: 20 AN: 67906

Other (OTH) AF: 0.00810 AC: 17 AN: 2098

Alfa AF: 0.00670 Hom.: 7

Bravo AF: 0.0120

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.78
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

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: rs2228276; hg19: chr19-58579640; COSMIC: COSV57879723; COSMIC: COSV57879723;