chr3-14654523-C-G

Variant names:

• chr3-14654523-C-G
• rs371366392
• NM_016474.5:c.140C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016474.5(CCDC174):​c.140C>G​(p.Thr47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,464,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CCDC174 NM_016474.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.446
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018644303).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016474.5. 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
	CCDC174	NM_016474.5	MANE Select	c.140C>G	p.Thr47Ser	missense	Exon 2 of 11	NP_057558.3
	CCDC174	NM_001410719.1		c.140C>G	p.Thr47Ser	missense	Exon 2 of 9	NP_001397648.1	A0A0B4J1R8
	CCDC174	NR_135523.2		n.215C>G		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC174	ENST00000383794.7	TSL:1 MANE Select	c.140C>G	p.Thr47Ser	missense	Exon 2 of 11	ENSP00000373304.3	Q6PII3
	CCDC174	ENST00000465759.1	TSL:1	n.204C>G		non_coding_transcript_exon	Exon 2 of 7
	CCDC174	ENST00000303688.8	TSL:5	c.140C>G	p.Thr47Ser	missense	Exon 2 of 9	ENSP00000302344.7	A0A0B4J1R8

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152016 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 10 AN: 227942 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000673

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000114 AC: 149 AN: 1312526 Hom.: 1 Cov.: 20 AF XY: 0.000103 AC XY: 68 AN XY: 659932

African (AFR) AF: 0.00 AC: 0 AN: 29914

American (AMR) AF: 0.0000734 AC: 3 AN: 40874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24816

East Asian (EAS) AF: 0.00 AC: 0 AN: 38760

South Asian (SAS) AF: 0.00 AC: 0 AN: 79184

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4978

European-Non Finnish (NFE) AF: 0.000143 AC: 141 AN: 985698

Other (OTH) AF: 0.0000724 AC: 4 AN: 55264

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74390

African (AFR) AF: 0.0000241 AC: 1 AN: 41522

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000281 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000415 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.46
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.055	N
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.054
Sift	Benign	0.93	T
Sift4G	Benign	0.75	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.17		Gain of glycosylation at T46 (P = 0.0155)
MVP		0.11
MPC		0.081
ClinPred		0.020	T
GERP RS		3.6
Varity_R		0.027
gMVP		0.16
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs371366392; hg19: chr3-14696030;