chr9-113042876-G-T

Position:

• chr9-113042876-G-T

Variant summary

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

The NM_003408.3(ZFP37):​c.1742C>A​(p.Ala581Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZFP37 NM_003408.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

Genes affected

ZFP37 (HGNC:12863): (ZFP37 zinc finger protein) This gene encodes a transcription factor that belongs to a large family of zinc finger proteins. A similar protein in mouse is thought to play a role in regulating the structures of the nucleolus and centromere in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

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/exons	MANE	UniProt
ZFP37	NM_003408.3	c.1742C>A	p.Ala581Asp	missense_variant	4/4	ENST00000374227.8
ZFP37	NM_001282515.2	c.1787C>A	p.Ala596Asp	missense_variant	4/4
ZFP37	NM_001282518.2	c.1745C>A	p.Ala582Asp	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP37	ENST00000374227.8	c.1742C>A	p.Ala581Asp	missense_variant	4/4	1	NM_003408.3
ZFP37	ENST00000555206.5	c.1745C>A	p.Ala582Asp	missense_variant	4/4	1
ZFP37	ENST00000553380.1	c.1787C>A	p.Ala596Asp	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250922 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

May 14, 2024

The c.1742C>A (p.A581D) alteration is located in exon 4 (coding exon 4) of the ZFP37 gene. This alteration results from a C to A substitution at nucleotide position 1742, causing the alanine (A) at amino acid position 581 to be replaced by an aspartic acid (D). 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	0.86
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.54
MutPred		0.64		Gain of ubiquitination at K585 (P = 0.056);.;.;
MVP		0.58
MPC		0.55
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.79
gMVP		0.13

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: rs753420117; hg19: chr9-115805156;