rs144966144

Variant names:

• chr11-116779049-G-A
• rs144966144
• NM_003904.5:c.1256C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003904.5. 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
	ZPR1	NM_003904.5	MANE Select	c.1256C>T	p.Ala419Val	missense	Exon 14 of 14	NP_003895.1	O75312
	ZPR1	NM_001317086.2		c.1094C>T	p.Ala365Val	missense	Exon 13 of 13	NP_001304015.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPR1	ENST00000227322.8	TSL:1 MANE Select	c.1256C>T	p.Ala419Val	missense	Exon 14 of 14	ENSP00000227322.3	O75312
	ZPR1	ENST00000900046.1		c.1286C>T	p.Ala429Val	missense	Exon 14 of 14	ENSP00000570105.1
	ZPR1	ENST00000900049.1		c.1262C>T	p.Ala421Val	missense	Exon 14 of 14	ENSP00000570108.1

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

GnomAD2 exomes AF: 0.00521 AC: 1310 AN: 251304 AF XY: 0.00357

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 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

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0354 AC: 1584 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111978

Other (OTH) AF: 0.000729 AC: 44 AN: 60390

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

African (AFR) AF: 0.000337 AC: 14 AN: 41570

American (AMR) AF: 0.0193 AC: 295 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000444 Hom.: 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.6
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
Mutation Taster		=32/68	disease causing

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