14-88574802-G-C

Variant names:

• chr14-88574802-G-C
• rs1555398661
• NM_024824.5:c.971G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024824.5(ZC3H14):​c.971G>C​(p.Arg324Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R324Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZC3H14 NM_024824.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.42
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28948456).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H14	NM_024824.5	MANE Select	c.971G>C	p.Arg324Pro	missense	Exon 7 of 17	NP_079100.2
	ZC3H14	NM_001160103.2		c.971G>C	p.Arg324Pro	missense	Exon 7 of 17	NP_001153575.1	Q6PJT7-2
	ZC3H14	NM_001326310.2		c.971G>C	p.Arg324Pro	missense	Exon 7 of 17	NP_001313239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H14	ENST00000251038.10	TSL:1 MANE Select	c.971G>C	p.Arg324Pro	missense	Exon 7 of 17	ENSP00000251038.5	Q6PJT7-1
	ZC3H14	ENST00000556000.5	TSL:1	c.716G>C	p.Arg239Pro	missense	Exon 3 of 13	ENSP00000451054.1	H0YJA2
	ZC3H14	ENST00000302216.12	TSL:1	c.971G>C	p.Arg324Pro	missense	Exon 7 of 14	ENSP00000307025.8	Q6PJT7-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.14		Gain of glycosylation at T325 (P = 0.0364)
MVP		0.082
MPC		0.52
ClinPred		0.84	D
GERP RS		5.7
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.27
gMVP		0.41
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555398661; hg19: chr14-89041146;