4-112548271-G-A

Position:

• chr4-112548271-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018392.5(ZGRF1):​c.5456C>T​(p.Ser1819Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZGRF1 NM_018392.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

Genes affected

ZGRF1 (HGNC:25654): (zinc finger GRF-type containing 1) The encoded protein contains GRF zinc finger (zf-GRF) and transmembrane domains. GRF zinc fingers are found in a number of DNA-binding proteins. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2017]

ZGRF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZGRF1	NM_018392.5	c.5456C>T	p.Ser1819Phe	missense_variant	23/28	ENST00000505019.6	NP_060862.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZGRF1	ENST00000505019.6	c.5456C>T	p.Ser1819Phe	missense_variant	23/28	5	NM_018392.5	ENSP00000424737.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399998 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Sep 01, 2021

The c.5456C>T (p.S1819F) alteration is located in exon 23 (coding exon 22) of the ZGRF1 gene. This alteration results from a C to T substitution at nucleotide position 5456, causing the serine (S) at amino acid position 1819 to be replaced by a phenylalanine (F). 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	0.63
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.7	M;M
PROVEAN	Pathogenic	-4.7	.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.83
MutPred		0.51		Loss of phosphorylation at S1819 (P = 0.076);Loss of phosphorylation at S1819 (P = 0.076);
MVP		0.66
MPC		0.42
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.67
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1182912659; hg19: chr4-113469427;