7-57120038-A-T

Variant names:

• chr7-57120038-A-T
• rs13235706
• NM_001370129.2:c.1377T>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001370129.2(ZNF479):​c.1377T>A​(p.His459Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,613,438 control chromosomes in the GnomAD database, including 19 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H459N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (19 hom.)
• Consequence: ZNF479 NM_001370129.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

ZNF479 (HGNC:23258): (zinc finger protein 479) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061730742).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00138 (210/152314) while in subpopulation EAS AF= 0.0259 (134/5168). AF 95% confidence interval is 0.0224. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF479	NM_001370129.2	c.1377T>A	p.His459Gln	missense_variant	Exon 4 of 4	ENST00000319636.10	NP_001357058.1
ZNF479	NM_033273.3	c.1377T>A	p.His459Gln	missense_variant	Exon 5 of 5		NP_150376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF479	ENST00000319636.10	c.1377T>A	p.His459Gln	missense_variant	Exon 4 of 4	1	NM_001370129.2	ENSP00000324518.6
ZNF479	ENST00000331162.8	c.1377T>A	p.His459Gln	missense_variant	Exon 5 of 5	1		ENSP00000333776.4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000860 AC: 213 AN: 247694 Hom.: 3 AF XY: 0.000839 AC XY: 113 AN XY: 134720

Gnomad AFR exome AF: 0.000473

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0109

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000444 AC: 649 AN: 1461124 Hom.: 19 Cov.: 31 AF XY: 0.000466 AC XY: 339 AN XY: 726904

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74470

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000719 Hom.: 0

ExAC AF: 0.000282 AC: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1377T>A (p.H459Q) alteration is located in exon 5 (coding exon 4) of the ZNF479 gene. This alteration results from a T to A substitution at nucleotide position 1377, causing the histidine (H) at amino acid position 459 to be replaced by a glutamine (Q). 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.49
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.5	D;.;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0040	B;B;.
Vest4		0.31
MutPred		0.90		Loss of ubiquitination at K456 (P = 0.0863);Loss of ubiquitination at K456 (P = 0.0863);.;
MVP		0.36
MPC		1.6
ClinPred		0.18	T
GERP RS		-1.9
Varity_R		0.032
gMVP		0.035

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: rs13235706; hg19: chr7-57187745;