19-57578676-G-A

Position:

• chr19-57578676-G-A

Variant summary

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

The NM_017879.3(ZNF416):​c.29C>T​(p.Thr10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,556,706 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: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ZNF416 NM_017879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.782

Genes affected

ZNF416 (HGNC:20645): (zinc finger protein 416) 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 by RNA polymerase II. Predicted to act upstream of or within cardiac muscle hypertrophy; negative regulation of cell growth involved in cardiac muscle cell development; and negative regulation of protein phosphorylation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZIK1 (HGNC:33104): (zinc finger protein interacting with K protein 1) 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 by RNA polymerase II. Predicted to be active 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=0.005069852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF416	NM_017879.3	c.29C>T	p.Thr10Ile	missense_variant	1/4	ENST00000196489.4	NP_060349.1
ZNF416	NM_001353405.2	c.-61C>T		5_prime_UTR_variant	1/3		NP_001340334.1
ZNF416	XM_024451594.2	c.-114C>T		5_prime_UTR_variant	1/5		XP_024307362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF416	ENST00000196489.4	c.29C>T	p.Thr10Ile	missense_variant	1/4	1	NM_017879.3	ENSP00000196489	P1
ZIK1	ENST00000598726.1	n.221G>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000406 AC: 73 AN: 179746 Hom.: 0 AF XY: 0.000447 AC XY: 44 AN XY: 98358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000457

Gnomad ASJ exome AF: 0.00409

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000312 AC: 438 AN: 1404348 Hom.: 0 Cov.: 30 AF XY: 0.000342 AC XY: 238 AN XY: 696044

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000756

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000223

Gnomad4 OTH exome AF: 0.000676

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74500

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000771 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000253 AC: 30

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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 22, 2021

The c.29C>T (p.T10I) alteration is located in exon 1 (coding exon 1) of the ZNF416 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the threonine (T) at amino acid position 10 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.0080
Sift	Benign	0.080	T
Sift4G	Benign	0.16	T
Polyphen		0.022	B
Vest4		0.12
MVP		0.055
MPC		0.26
ClinPred		0.031	T
GERP RS		1.5
Varity_R		0.038
gMVP		0.14

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: rs138550315; hg19: chr19-58090044;