4-112541153-C-A

Variant names:

• chr4-112541153-C-A
• rs574383993
• NM_018392.5:c.5714G>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.5714G>T​(p.Arg1905Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1905Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZGRF1 NM_018392.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.38
• 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, 0.768

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.5714G>T	p.Arg1905Leu	missense	Exon 25 of 28	NP_060862.3
	ZGRF1	NM_001350397.2		c.5540G>T	p.Arg1847Leu	missense	Exon 24 of 27	NP_001337326.1
	NEUROG2-AS1	NR_161159.1		n.513-5632C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZGRF1	ENST00000505019.6	TSL:5 MANE Select	c.5714G>T	p.Arg1905Leu	missense	Exon 25 of 28	ENSP00000424737.1	Q86YA3-1
	ZGRF1	ENST00000445203.6	TSL:5	c.5714G>T	p.Arg1905Leu	missense	Exon 24 of 27	ENSP00000390505.3	Q86YA3-1
	ZGRF1	ENST00000925931.1		c.5540G>T	p.Arg1847Leu	missense	Exon 24 of 27	ENSP00000595990.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.4
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.59
MutPred		0.45		Loss of solvent accessibility (P = 0.1922)
MVP		0.68
MPC		0.45
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.63
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs574383993; hg19: chr4-113462309;