14-68789724-T-C

Variant names:

• chr14-68789724-T-C
• rs765865743
• NM_004926.4:c.826A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004926.4(ZFP36L1):​c.826A>G​(p.Thr276Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ZFP36L1 NM_004926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.172

Genes affected

ZFP36L1 (HGNC:1107): (ZFP36 ring finger protein like 1) This gene is a member of the TIS11 family of early response genes, which are induced by various agonists such as the phorbol ester TPA and the polypeptide mitogen EGF. This gene is well conserved across species and has a promoter that contains motifs seen in other early-response genes. The encoded protein contains a distinguishing putative zinc finger domain with a repeating cys-his motif. This putative nuclear transcription factor most likely functions in regulating the response to growth factors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027886748).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP36L1	NM_004926.4	c.826A>G	p.Thr276Ala	missense_variant	Exon 2 of 2	ENST00000439696.3	NP_004917.2
ZFP36L1	NM_001244701.1	c.1033A>G	p.Thr345Ala	missense_variant	Exon 3 of 3		NP_001231630.1
ZFP36L1	NM_001244698.2	c.826A>G	p.Thr276Ala	missense_variant	Exon 2 of 3		NP_001231627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP36L1	ENST00000439696.3	c.826A>G	p.Thr276Ala	missense_variant	Exon 2 of 2	1	NM_004926.4	ENSP00000388402.2

Frequencies

GnomAD3 genomes AF: 0.0000661 AC: 10 AN: 151230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000738

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.0000880 AC: 22 AN: 249896 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000661 AC: 10 AN: 151230 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73816

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.0000584 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826A>G (p.T276A) alteration is located in exon 2 (coding exon 2) of the ZFP36L1 gene. This alteration results from a A to G substitution at nucleotide position 826, causing the threonine (T) at amino acid position 276 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.69
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.019
Sift	Benign	0.52	T;T
Sift4G	Benign	0.92	T;T
Polyphen		0.0040	B;B
Vest4		0.063
MVP		0.093
MPC		1.1
ClinPred		0.024	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.27

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: rs765865743; hg19: chr14-69256441;