19-37185619-C-T

Position:

• chr19-37185619-C-T

Variant summary

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

The ENST00000532828.7(ZNF585B):​c.1918G>A​(p.Gly640Arg) 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: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF585B ENST00000532828.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

Genes affected

ZNF585B (HGNC:30948): (zinc finger protein 585B) Predicted to enable DNA-binding transcription activator 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]

ENSG00000267360 (HGNC:):

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	Protein	UniProt
ZNF585B	NM_152279.4	c.1918G>A	p.Gly640Arg	missense_variant	5/5	ENST00000532828.7	NP_689492.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF585B	ENST00000532828.7	c.1918G>A	p.Gly640Arg	missense_variant	5/5	1	NM_152279.4	ENSP00000433773.1
ENSG00000267360	ENST00000588873.1	c.33+21421G>A		intron_variant		5		ENSP00000465212.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000227

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 27, 2022

The c.1918G>A (p.G640R) alteration is located in exon 5 (coding exon 4) of the ZNF585B gene. This alteration results from a G to A substitution at nucleotide position 1918, causing the glycine (G) at amino acid position 640 to be replaced by an arginine (R). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.075	T;D
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.67		Gain of MoRF binding (P = 0.0275);.;
MVP		0.71
MPC		1.1
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.35
gMVP		0.060

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: rs1972324516; hg19: chr19-37676521;