1-71078658-C-A

Variant names:

• chr1-71078658-C-A
• rs531204550
• NM_203350.3:c.107G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_203350.3(ZRANB2):​c.107G>T​(p.Arg36Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R36Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZRANB2 NM_203350.3 missense, splice_region
• Scores: Splicing: ADA: 0.9902
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• Publications: 0 publications found

Genes affected

ZRANB2 (HGNC:13058): (zinc finger RANBP2-type containing 2) Enables RNA binding activity. Predicted to be involved in RNA splicing and mRNA processing. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZRANB2	NM_203350.3	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 10	ENST00000370920.8	NP_976225.1
ZRANB2	NM_005455.5	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 11		NP_005446.2
ZRANB2	XM_047434733.1	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 10		XP_047290689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZRANB2	ENST00000370920.8	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 10	1	NM_203350.3	ENSP00000359958.3
ZRANB2	ENST00000254821.10	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 11	1		ENSP00000254821.6
ZRANB2	ENST00000611683.1	c.107G>T	p.Arg36Leu	missense_variant, splice_region_variant	Exon 2 of 10	2		ENSP00000482026.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.0	M;M;M
PhyloP100		5.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D;D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.99	D;P;P
Vest4		0.70
MutPred		0.42		Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);
MVP		0.47
MPC		2.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.49
gMVP		0.96
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
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: rs531204550; hg19: chr1-71544341;