12-133106271-A-C

Position:

• chr12-133106271-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003440.4(ZNF140):​c.994A>C​(p.Asn332His) 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 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: ZNF140 NM_003440.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32

Genes affected

ZNF140 (HGNC:12925): (zinc finger protein 140) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF891 (HGNC:38709): (zinc finger protein 891) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06272009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF140	NM_003440.4	c.994A>C	p.Asn332His	missense_variant	5/5	ENST00000355557.7	NP_003431.2
ZNF891	NM_001277291.2	c.*14013T>G		3_prime_UTR_variant	2/2	ENST00000537226.3	NP_001264220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF140	ENST00000355557.7	c.994A>C	p.Asn332His	missense_variant	5/5	1	NM_003440.4	ENSP00000347755.2
ZNF891	ENST00000537226	c.*14013T>G		3_prime_UTR_variant	2/2	2	NM_001277291.2	ENSP00000437590.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 19, 2024

The c.994A>C (p.N332H) alteration is located in exon 5 (coding exon 4) of the ZNF140 gene. This alteration results from a A to C substitution at nucleotide position 994, causing the asparagine (N) at amino acid position 332 to be replaced by a histidine (H). 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	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.11	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.13	N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.024
Sift	Uncertain	0.024	D;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.47	P;.
Vest4		0.16
MutPred		0.30		Gain of disorder (P = 0.0735);.;
MVP		0.085
MPC		0.44
ClinPred		0.11	T
GERP RS		-2.6
Varity_R		0.15
gMVP		0.028

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: rs1955590757; hg19: chr12-133682857;