3-14654495-T-G

Position:

• chr3-14654495-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016474.5(CCDC174):​c.112T>G​(p.Ser38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000964 in 1,453,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CCDC174 NM_016474.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032522798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC174	NM_016474.5	c.112T>G	p.Ser38Ala	missense_variant	2/11	ENST00000383794.7	NP_057558.3
CCDC174	NM_001410719.1	c.112T>G	p.Ser38Ala	missense_variant	2/9		NP_001397648.1
CCDC174	XM_017006555.3	c.112T>G	p.Ser38Ala	missense_variant	2/8		XP_016862044.1
CCDC174	NR_135523.2	n.187T>G		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC174	ENST00000383794.7	c.112T>G	p.Ser38Ala	missense_variant	2/11	1	NM_016474.5	ENSP00000373304.3
CCDC174	ENST00000465759.1	n.176T>G		non_coding_transcript_exon_variant	2/7	1
CCDC174	ENST00000303688.8	c.112T>G	p.Ser38Ala	missense_variant	2/9	5		ENSP00000302344.7
CCDC174	ENST00000463438.5	n.185T>G		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000964 AC: 14 AN: 1453010 Hom.: 0 Cov.: 28 AF XY: 0.00000968 AC XY: 7 AN XY: 722898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.112T>G (p.S38A) alteration is located in exon 2 (coding exon 2) of the CCDC174 gene. This alteration results from a T to G substitution at nucleotide position 112, causing the serine (S) at amino acid position 38 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	0.052
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.44
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.099
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.22		Loss of ubiquitination at K36 (P = 0.0547);Loss of ubiquitination at K36 (P = 0.0547);
MVP		0.17
MPC		0.075
ClinPred		0.12	T
GERP RS		-1.7
Varity_R		0.040
gMVP		0.089

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: rs2030883672; hg19: chr3-14696002;