14-88620769-G-T

Position:

• chr14-88620769-G-T

Variant summary

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

The NM_183387.3(EML5):​c.5360C>A​(p.Ala1787Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,596,626 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (41 hom.)
• Consequence: EML5 NM_183387.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.77

Genes affected

EML5 (HGNC:18197): (EMAP like 5) Predicted to enable microtubule binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071484447).
• BP6: Variant 14-88620769-G-T is Benign according to our data. Variant chr14-88620769-G-T is described in ClinVar as [Benign]. Clinvar id is 709293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1606/152062) while in subpopulation AFR AF= 0.0372 (1542/41464). AF 95% confidence interval is 0.0356. There are 28 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EML5	NM_183387.3	c.5360C>A	p.Ala1787Glu	missense_variant	39/44	ENST00000554922.6
ZC3H14	NM_024824.5	c.*9018G>T		3_prime_UTR_variant	17/17	ENST00000251038.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EML5	ENST00000554922.6	c.5360C>A	p.Ala1787Glu	missense_variant	39/44	5	NM_183387.3	P4
ZC3H14	ENST00000251038.10	c.*9018G>T		3_prime_UTR_variant	17/17	1	NM_024824.5	P3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1600 AN: 151944 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00241 AC: 561 AN: 232492 Hom.: 7 AF XY: 0.00197 AC XY: 248 AN XY: 126190

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000746

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000466

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00104 AC: 1505 AN: 1444564 Hom.: 41 Cov.: 30 AF XY: 0.000904 AC XY: 649 AN XY: 718128

Gnomad4 AFR exome AF: 0.0391

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000728

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000380

Gnomad4 OTH exome AF: 0.00203

GnomAD4 genome AF: 0.0106 AC: 1606 AN: 152062 Hom.: 28 Cov.: 31 AF XY: 0.0102 AC XY: 761 AN XY: 74352

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00163 Hom.: 4

Bravo AF: 0.0114

ESP6500AA AF: 0.0302 AC: 112

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00282 AC: 341

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.010	D;D;T
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.87	.;P;.
Vest4		0.61
MVP		0.75
MPC		0.86
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76231557; hg19: chr14-89087113;