4-112548271-G-A

Variant names:

• chr4-112548271-G-A
• rs1182912659
• NM_018392.5:c.5456C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

NEUROG2-AS1 (HGNC:40656): (NEUROG2 and ZGRF1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018392.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZGRF1	NM_018392.5	MANE Select	c.5456C>T	p.Ser1819Phe	missense	Exon 23 of 28	NP_060862.3
	ZGRF1	NM_001350397.2		c.5282C>T	p.Ser1761Phe	missense	Exon 22 of 27	NP_001337326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZGRF1	ENST00000505019.6	TSL:5 MANE Select	c.5456C>T	p.Ser1819Phe	missense	Exon 23 of 28	ENSP00000424737.1	Q86YA3-1
	ZGRF1	ENST00000445203.6	TSL:5	c.5456C>T	p.Ser1819Phe	missense	Exon 22 of 27	ENSP00000390505.3	Q86YA3-1
	ZGRF1	ENST00000925931.1		c.5282C>T	p.Ser1761Phe	missense	Exon 22 of 27	ENSP00000595990.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079060

Other (OTH) AF: 0.00 AC: 0 AN: 58198

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.8
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.83
MutPred		0.51		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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1182912659; hg19: chr4-113469427;