chr4-112554756-A-C

Position:

• chr4-112554756-A-C

Variant summary

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

The ENST00000612287.4(ZGRF1):​c.-321T>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000131 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: ZGRF1 ENST00000612287.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

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 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
ZGRF1	NM_018392.5	c.5147T>G	p.Phe1716Cys	missense_variant	21/28	ENST00000505019.6	NP_060862.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZGRF1	ENST00000505019.6	c.5147T>G	p.Phe1716Cys	missense_variant	21/28	5	NM_018392.5	ENSP00000424737.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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.: 25

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

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: 0.0000151

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

Apr 27, 2022

The c.5147T>G (p.F1716C) alteration is located in exon 21 (coding exon 20) of the ZGRF1 gene. This alteration results from a T to G substitution at nucleotide position 5147, causing the phenylalanine (F) at amino acid position 1716 to be replaced by a cysteine (C). 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	0.89
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.1	M;M
PROVEAN	Pathogenic	-6.4	.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.48
MutPred		0.56		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.67
MPC		0.48
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.73
gMVP		0.38

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: rs1421512090; hg19: chr4-113475912;