chr11-116779049-G-A

Position:

• chr11-116779049-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003904.5(ZPR1):​c.1256C>T​(p.Ala419Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,048 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (44 hom.)
• Consequence: ZPR1 NM_003904.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.60

Genes affected

ZPR1 (HGNC:13051): (ZPR1 zinc finger) The protein encoded by this gene is found in the cytoplasm of quiescent cells but translocates to the nucleolus in proliferating cells. The encoded protein interacts with survival motor neuron protein (SMN1) to enhance pre-mRNA splicing and to induce neuronal differentiation and axonal growth. Defects in this gene or the SMN1 gene can cause spinal muscular atrophy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009350061).
• BP6: Variant 11-116779049-G-A is Benign according to our data. Variant chr11-116779049-G-A is described in ClinVar as [Benign]. Clinvar id is 778441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00208 (317/152292) while in subpopulation AMR AF= 0.0193 (295/15302). AF 95% confidence interval is 0.0175. There are 6 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZPR1	NM_003904.5	c.1256C>T	p.Ala419Val	missense_variant	14/14	ENST00000227322.8	NP_003895.1
ZPR1	NM_001317086.2	c.1094C>T	p.Ala365Val	missense_variant	13/13		NP_001304015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPR1	ENST00000227322.8	c.1256C>T	p.Ala419Val	missense_variant	14/14	1	NM_003904.5	ENSP00000227322	P1
ZPR1	ENST00000444935.5	c.1169C>T	p.Ala390Val	missense_variant	13/13	5		ENSP00000390391
ZPR1	ENST00000429220.5	c.1037C>T	p.Ala346Val	missense_variant	12/12	5		ENSP00000394495

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152174 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

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: 0.00382

GnomAD3 exomes AF: 0.00521 AC: 1310 AN: 251304 Hom.: 35 AF XY: 0.00357 AC XY: 485 AN XY: 135828

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00114 AC: 1666 AN: 1461756 Hom.: 44 Cov.: 31 AF XY: 0.000898 AC XY: 653 AN XY: 727184

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0354

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: 0.0000270

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152292 Hom.: 6 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74458

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0193

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: 0.00378

Alfa AF: 0.000246 Hom.: 1

Bravo AF: 0.00360

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00386 AC: 469

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.20	T
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.61
MVP		0.68
MPC		0.39
ClinPred		0.099	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.70

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: rs144966144; hg19: chr11-116649765; COSMIC: COSV105846480; COSMIC: COSV105846480;