chr4-372790-A-G

Position:

• chr4-372790-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003441.4(ZNF141):​c.353A>G​(p.Lys118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF141 NM_003441.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.406

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0686132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF141	NM_003441.4	c.353A>G	p.Lys118Arg	missense_variant	4/4	ENST00000240499.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF141	ENST00000240499.8	c.353A>G	p.Lys118Arg	missense_variant	4/4	1	NM_003441.4	P1
ZNF141	ENST00000512994.5	c.353A>G	p.Lys118Arg	missense_variant	4/5	1
ZNF141	ENST00000505939.5	c.227-10305A>G		intron_variant		5
ZNF141	ENST00000366506.4	n.300A>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.353A>G (p.K118R) alteration is located in exon 4 (coding exon 4) of the ZNF141 gene. This alteration results from a A to G substitution at nucleotide position 353, causing the lysine (K) at amino acid position 118 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.0
DANN	Uncertain	0.99
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.064
Sift	Benign	0.057	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.35	B;B
Vest4		0.057
MutPred		0.32		Loss of methylation at K118 (P = 0.0015);Loss of methylation at K118 (P = 0.0015);
MVP		0.28
MPC		0.33
ClinPred		0.26	T
GERP RS		0.89
Varity_R		0.050
gMVP		0.0092

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

Publications

LitVar

Other links and lift over

dbSNP: rs1712134268; hg19: chr4-366579;