19-43607698-G-C

Position:

• chr19-43607698-G-C

Variant summary

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

The NM_182498.4(ZNF428):​c.486C>G​(p.His162Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF428 NM_182498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

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=0.1621778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF428	NM_182498.4	c.486C>G	p.His162Gln	missense_variant	3/3	ENST00000300811.8	NP_872304.2
ZNF428	XM_047438168.1	c.486C>G	p.His162Gln	missense_variant	4/4		XP_047294124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF428	ENST00000300811.8	c.486C>G	p.His162Gln	missense_variant	3/3	1	NM_182498.4	ENSP00000300811	P1
ZNF428	ENST00000598676.1	c.585C>G	p.His195Gln	missense_variant	4/4	5		ENSP00000469484
SRRM5	ENST00000607544.1	c.-95-4329G>C		intron_variant		2		ENSP00000476253	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

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

Jan 05, 2022

The c.486C>G (p.H162Q) alteration is located in exon 3 (coding exon 2) of the ZNF428 gene. This alteration results from a C to G substitution at nucleotide position 486, causing the histidine (H) at amino acid position 162 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	Benign	0.25
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.97	N;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Benign	0.28
Sift	Benign	0.049	D;.
Sift4G	Benign	0.38	T;.
Polyphen		0.0	B;.
Vest4		0.17
MutPred		0.39		Loss of catalytic residue at H162 (P = 0.0331);.;
MVP		0.043
MPC		0.39
ClinPred		0.43	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44111850;