4-372823-G-A

Position:

• chr4-372823-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000240499.8(ZNF141):​c.386G>A​(p.Gly129Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,382 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: ZNF141 ENST00000240499.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0400

Genes affected

ZNF141 (HGNC:12926): (zinc finger protein 141) The protein encoded by this gene is a zinc finger protein that may be a tumor suppressor. Defects in this gene have been associated with autosomal recessive postaxial polydactyly type A. [provided by RefSeq, Jan 2017]

ZNF141 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008481622).
• BP6: Variant 4-372823-G-A is Benign according to our data. Variant chr4-372823-G-A is described in ClinVar as [Benign]. Clinvar id is 718907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF141	NM_003441.4	c.386G>A	p.Gly129Asp	missense_variant	4/4	ENST00000240499.8	NP_003432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF141	ENST00000240499.8	c.386G>A	p.Gly129Asp	missense_variant	4/4	1	NM_003441.4	ENSP00000240499.7
ZNF141	ENST00000512994.5	c.386G>A	p.Gly129Asp	missense_variant	4/5	1		ENSP00000425799.1
ZNF141	ENST00000505939.5	c.227-10272G>A		intron_variant		5		ENSP00000424403.1
ZNF141	ENST00000366506.4	n.333G>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00191 AC: 478 AN: 250732 Hom.: 0 AF XY: 0.00178 AC XY: 242 AN XY: 135578

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00157 AC: 2296 AN: 1461084 Hom.: 4 Cov.: 31 AF XY: 0.00158 AC XY: 1149 AN XY: 726806

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74478

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00258 Hom.: 0

Bravo AF: 0.00186

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00180 AC: 218

EpiCase AF: 0.00338

EpiControl AF: 0.00255

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

ZNF141-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.00076	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.066
Sift	Benign	0.11	T;T
Sift4G	Benign	0.063	T;T
Polyphen		1.0	D;D
Vest4		0.16
MVP		0.33
MPC		0.46
ClinPred		0.091	T
GERP RS		1.2
Varity_R		0.14
gMVP		0.0051

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

Publications

LitVar

Other links and lift over

dbSNP: rs138386005; hg19: chr4-366612;