16-68558035-C-T

Variant names:

• chr16-68558035-C-T
• rs1287309187
• NM_001305203.2:c.71C>T

Variant summary

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

The NM_001305203.2(ZFP90):​c.71C>T​(p.Thr24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: ZFP90 NM_001305203.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.885

Genes affected

ZFP90 (HGNC:23329): (ZFP90 zinc finger protein) This gene encodes a member of the zinc finger protein family that modulates gene expression. The encoded protein derepresses the transcription of certain fetal cardiac genes and may contribute to the genetic reprogramming that occurs during the development of heart failure. Genome wide association studies have identified this gene among ulcerative colitis risk loci. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP90	NM_001305203.2	c.71C>T	p.Thr24Ile	missense_variant	Exon 3 of 5	ENST00000563169.7	NP_001292132.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP90	ENST00000563169.7	c.71C>T	p.Thr24Ile	missense_variant	Exon 3 of 5	1	NM_001305203.2	ENSP00000454418.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74112

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>T (p.T24I) alteration is located in exon 2 (coding exon 2) of the ZFP90 gene. This alteration results from a C to T substitution at nucleotide position 71, causing the threonine (T) at amino acid position 24 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	.;.;T;T;.;.;.;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.27	T;T;.;.;T;.;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	.;.;M;M;.;.;.;M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.1	.;.;.;D;.;D;.;.;D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0010	.;.;.;D;.;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;.;.;D;.
Vest4		0.77, 0.77, 0.76, 0.76
MutPred		0.75		Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);Gain of catalytic residue at T24 (P = 0.0279);.;
MVP		0.64
MPC		0.57
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1287309187; hg19: chr16-68591938;