19-58434836-C-T

Variant names:

• chr19-58434836-C-T
• rs1122955
• NM_003433.4:c.608G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003433.4(ZNF132):​c.608G>A​(p.Gly203Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,614,012 control chromosomes in the GnomAD database, including 33,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G203S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2535 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31131 hom.)
• Consequence: ZNF132 NM_003433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.81
• Publications: 27 publications found

Genes affected

ZNF132 (HGNC:12916): (zinc finger protein 132) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF324B (HGNC:33107): (zinc finger protein 324B) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052083135).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF132	NM_003433.4	c.608G>A	p.Gly203Asp	missense_variant	Exon 3 of 3	ENST00000254166.4	NP_003424.3
ZNF132	XM_047439361.1	c.569G>A	p.Gly190Asp	missense_variant	Exon 3 of 3		XP_047295317.1
ZNF324B	XM_047438807.1	c.-5-4605C>T		intron_variant	Intron 1 of 4		XP_047294763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF132	ENST00000254166.4	c.608G>A	p.Gly203Asp	missense_variant	Exon 3 of 3	1	NM_003433.4	ENSP00000254166.2
ZNF132	ENST00000599148.1	n.749G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ZNF132	ENST00000703732.1	n.1074G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26404 AN: 152032 Hom.: 2534 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.182 AC: 45815 AN: 251374 AF XY: 0.189

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0635

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.202 AC: 295864 AN: 1461862 Hom.: 31131 Cov.: 36 AF XY: 0.204 AC XY: 148176 AN XY: 727238

African (AFR) AF: 0.104 AC: 3493 AN: 33480

American (AMR) AF: 0.136 AC: 6074 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5231 AN: 26134

East Asian (EAS) AF: 0.0523 AC: 2078 AN: 39700

South Asian (SAS) AF: 0.190 AC: 16412 AN: 86258

European-Finnish (FIN) AF: 0.235 AC: 12536 AN: 53412

Middle Eastern (MID) AF: 0.208 AC: 1202 AN: 5766

European-Non Finnish (NFE) AF: 0.213 AC: 237128 AN: 1111996

Other (OTH) AF: 0.194 AC: 11710 AN: 60396

GnomAD4 genome AF: 0.174 AC: 26424 AN: 152150 Hom.: 2535 Cov.: 32 AF XY: 0.171 AC XY: 12748 AN XY: 74374

African (AFR) AF: 0.105 AC: 4377 AN: 41506

American (AMR) AF: 0.164 AC: 2499 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3466

East Asian (EAS) AF: 0.0608 AC: 315 AN: 5178

South Asian (SAS) AF: 0.174 AC: 838 AN: 4816

European-Finnish (FIN) AF: 0.233 AC: 2461 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14588 AN: 67998

Other (OTH) AF: 0.160 AC: 339 AN: 2116

Alfa AF: 0.196 Hom.: 12479

Bravo AF: 0.165

TwinsUK AF: 0.217 AC: 804

ALSPAC AF: 0.209 AC: 807

ESP6500AA AF: 0.108 AC: 477

ESP6500EA AF: 0.205 AC: 1761

ExAC AF: 0.184 AC: 22374

Asia WGS AF: 0.123 AC: 428 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.214

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0050
DANN	Benign	0.27
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00043	N
LIST_S2	Benign	0.019	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.36	N
PhyloP100		-3.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.010
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.013
ClinPred		0.00080	T
GERP RS		0.23
Varity_R		0.037
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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: rs1122955; hg19: chr19-58946203; COSMIC: COSV54235016; COSMIC: COSV54235016;