3-14661587-G-A

Position:

chr3-14661587-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016474.5(CCDC174):c.365G>A(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,614,108 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0049 ( 39 hom. )

Consequence

CCDC174
NM_016474.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

CCDC174 (HGNC:28033): (coiled-coil domain containing 174) The protein encoded by this gene is found in the nucleus, where it interacts with eukaryotic translation initiation factor 4A, isoform 3. The encoded protein appears to be a part of the exon junction complex, which is involved in RNA processing, translation, and nonsense-mediated mRNA decay. A mutation in this gene has been associated with infantile hypotonia with psychomotor retardation. [provided by RefSeq, Mar 2016]

CCDC174 links:

LOC124906215 (HGNC:):

LOC124906215 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043236315).

BP6

Variant 3-14661587-G-A is Benign according to our data. Variant chr3-14661587-G-A is described in ClinVar as [Benign]. Clinvar id is 790261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00495 (7234/1461746) while in subpopulation SAS AF= 0.0162 (1399/86244). AF 95% confidence interval is 0.0155. There are 39 homozygotes in gnomad4_exome. There are 3984 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC174	NM_016474.5 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	5/11	ENST00000383794.7	NP_057558.3
LOC124906215	XR_007095827.1 linkuse as main transcript	n.427-2397C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CCDC174	ENST00000383794.7 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	5/11	1	NM_016474.5	ENSP00000373304	P1
CCDC174	ENST00000465759.1 linkuse as main transcript	n.429G>A		non_coding_transcript_exon_variant	5/7	1
CCDC174	ENST00000303688.8 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	5/9	5		ENSP00000302344
CCDC174	ENST00000463438.5 linkuse as main transcript	n.438G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

597

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00484

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00549

AC:

1379

AN:

251354

Hom.:

AF XY:

0.00636

AC XY:

864

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00399

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0154

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00495

AC:

7234

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

3984

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00461

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0162

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.00426

Gnomad4 OTH exome

AF:

0.00540

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152362

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0170

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00484

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00479

Hom.:

Bravo

AF:

0.00361

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00551

AC:

669

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00605

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CCDC174-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.026

T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;L;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.041

Sift

Benign

0.19

.;T;T

Sift4G

Benign

0.080

T;T;T

Polyphen

0.011

.;B;.

Vest4

0.16

MVP

0.64

MPC

0.20

ClinPred

0.014

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over