12-53186499-G-T

Variant names:

• chr12-53186499-G-T
• rs370571232
• NM_001004304.4:c.482G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001004304.4(ZNF740):​c.482G>T​(p.Arg161Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R161Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ZNF740 NM_001004304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 0 publications found

Genes affected

ZNF740 (HGNC:27465): (zinc finger protein 740) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34285623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF740	NM_001004304.4	c.482G>T	p.Arg161Leu	missense_variant	Exon 6 of 7	ENST00000416904.5	NP_001004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF740	ENST00000416904.5	c.482G>T	p.Arg161Leu	missense_variant	Exon 6 of 7	1	NM_001004304.4	ENSP00000409463.2
ZNF740	ENST00000549739.1	n.325G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414008 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698698

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32384

American (AMR) AF: 0.00 AC: 0 AN: 37354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 37168

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086662

Other (OTH) AF: 0.00 AC: 0 AN: 58704

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.56	N
PhyloP100		2.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.066	T
Sift4G	Benign	0.50	T
Polyphen		0.96	D
Vest4		0.66
MutPred		0.46		Loss of MoRF binding (P = 0.0219);
MVP		0.13
MPC		0.92
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.59
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370571232; hg19: chr12-53580283;