chr14-88575836-T-G

Variant names:

• chr14-88575836-T-G
• rs1469602
• NM_024824.5:c.1023-4T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024824.5(ZC3H14):​c.1023-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,609,752 control chromosomes in the GnomAD database, including 392,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (28777 hom., cov: 32)
  • Exomes 𝑓: 0.70 (363285 hom.)
• Consequence: ZC3H14 NM_024824.5 splice_region, intron
• Scores: Splicing: ADA: 0.005529
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.04
• Publications: 20 publications found

Genes affected

ZC3H14 (HGNC:20509): (zinc finger CCCH-type containing 14) The protein encoded by this gene is a poly(A)-binding protein that can affect gene expression and poly(A) tail length. The encoded protein may influence mRNA stability, nuclear export, and translation. [provided by RefSeq, May 2016]

ZC3H14 Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• intellectual disability, autosomal recessive 56

  Inheritance: AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-88575836-T-G is Benign according to our data. Variant chr14-88575836-T-G is described in ClinVar as Benign. ClinVar VariationId is 130765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024824.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H14	NM_024824.5	MANE Select	c.1023-4T>G		splice_region intron	N/A	NP_079100.2
	ZC3H14	NM_001160103.2		c.1023-4T>G		splice_region intron	N/A	NP_001153575.1
	ZC3H14	NM_001326310.2		c.1023-4T>G		splice_region intron	N/A	NP_001313239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H14	ENST00000251038.10	TSL:1 MANE Select	c.1023-4T>G		splice_region intron	N/A	ENSP00000251038.5
	ZC3H14	ENST00000556000.5	TSL:1	c.768-4T>G		splice_region intron	N/A	ENSP00000451054.1
	ZC3H14	ENST00000302216.12	TSL:1	c.1023-4T>G		splice_region intron	N/A	ENSP00000307025.8

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89159 AN: 151866 Hom.: 28767 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.613

GnomAD2 exomes AF: 0.616 AC: 154469 AN: 250890 AF XY: 0.628

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.667

Gnomad EAS exome AF: 0.344

Gnomad FIN exome AF: 0.783

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.697 AC: 1015962 AN: 1457768 Hom.: 363285 Cov.: 32 AF XY: 0.696 AC XY: 504765 AN XY: 725516

African (AFR) AF: 0.315 AC: 10512 AN: 33366

American (AMR) AF: 0.440 AC: 19672 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 17550 AN: 26104

East Asian (EAS) AF: 0.352 AC: 13937 AN: 39620

South Asian (SAS) AF: 0.576 AC: 49645 AN: 86174

European-Finnish (FIN) AF: 0.779 AC: 41376 AN: 53096

Middle Eastern (MID) AF: 0.609 AC: 3482 AN: 5720

European-Non Finnish (NFE) AF: 0.740 AC: 820031 AN: 1108748

Other (OTH) AF: 0.660 AC: 39757 AN: 60234

GnomAD4 genome AF: 0.587 AC: 89196 AN: 151984 Hom.: 28777 Cov.: 32 AF XY: 0.587 AC XY: 43650 AN XY: 74314

African (AFR) AF: 0.328 AC: 13605 AN: 41440

American (AMR) AF: 0.530 AC: 8090 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2318 AN: 3472

East Asian (EAS) AF: 0.377 AC: 1945 AN: 5160

South Asian (SAS) AF: 0.595 AC: 2854 AN: 4798

European-Finnish (FIN) AF: 0.791 AC: 8364 AN: 10574

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49988 AN: 67978

Other (OTH) AF: 0.613 AC: 1292 AN: 2108

Alfa AF: 0.678 Hom.: 147275

Bravo AF: 0.552

Asia WGS AF: 0.463 AC: 1611 AN: 3478

EpiCase AF: 0.717

EpiControl AF: 0.717

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.5
DANN	Benign	0.64
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0055
dbscSNV1_RF	Benign	0.15
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: rs1469602; hg19: chr14-89042180; COSMIC: COSV51769735; COSMIC: COSV51769735;