chr3-14654426-T-G

Position:

• chr3-14654426-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016474.5(CCDC174):​c.43T>G​(p.Leu15Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC174 NM_016474.5 missense, splice_region
• Scores: Splicing: ADA: 0.01027
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.603

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC174	NM_016474.5	c.43T>G	p.Leu15Val	missense_variant, splice_region_variant	2/11	ENST00000383794.7	NP_057558.3
CCDC174	NM_001410719.1	c.43T>G	p.Leu15Val	missense_variant, splice_region_variant	2/9		NP_001397648.1
CCDC174	XM_017006555.3	c.43T>G	p.Leu15Val	missense_variant, splice_region_variant	2/8		XP_016862044.1
CCDC174	NR_135523.2	n.118T>G		splice_region_variant, non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC174	ENST00000383794.7	c.43T>G	p.Leu15Val	missense_variant, splice_region_variant	2/11	1	NM_016474.5	ENSP00000373304.3
CCDC174	ENST00000465759.1	n.107T>G		splice_region_variant, non_coding_transcript_exon_variant	2/7	1
CCDC174	ENST00000303688.8	c.43T>G	p.Leu15Val	missense_variant, splice_region_variant	2/9	5		ENSP00000302344.7
CCDC174	ENST00000463438.5	n.116T>G		splice_region_variant, non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 23

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

Mar 01, 2023

The c.43T>G (p.L15V) 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 43, causing the leucine (L) at amino acid position 15 to be replaced by a valine (V). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.074	T;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.43		Gain of glycosylation at S14 (P = 0.0153);Gain of glycosylation at S14 (P = 0.0153);
MVP		0.83
MPC		0.092
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.19
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.14
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-14695933;