chr7-107563973-C-T

Position:

• chr7-107563973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181581.3(DUS4L):​c.-347C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000177 in 1,133,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: DUS4L NM_181581.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.203

Genes affected

DUS4L (HGNC:21517): (dihydrouridine synthase 4 like) Predicted to enable tRNA dihydrouridine synthase activity. Predicted to be involved in tRNA dihydrouridine synthesis. [provided by Alliance of Genome Resources, Apr 2022]

COG5 (HGNC:14857): (component of oligomeric golgi complex 5) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. The encoded protein is organized with conserved oligomeric Golgi complex components 6, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants. Mutations in this gene result in congenital disorder of glycosylation type 2I.[provided by RefSeq, Jan 2011]

DUS4L-BCAP29 (HGNC:54422): (DUS4L-BCAP29 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring DUS4L (dihydrouridine synthase 4 like) and BCAP29 (B cell receptor associated protein 29) genes on chromosome 7. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2019]

DUS4L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09735808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUS4L	NM_181581.3	c.-347C>T		5_prime_UTR_variant	1/8	ENST00000265720.8	NP_853559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUS4L	ENST00000265720	c.-347C>T		5_prime_UTR_variant	1/8	2	NM_181581.3	ENSP00000265720.3
DUS4L-BCAP29	ENST00000673757	c.-347C>T		5_prime_UTR_variant	1/15			ENSP00000501026.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000177 AC: 2 AN: 1133020 Hom.: 0 Cov.: 37 AF XY: 0.00000175 AC XY: 1 AN XY: 570320

Gnomad4 AFR exome AF: 0.0000367

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: 0.00000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

COG5-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 6 of the COG5 protein (p.Gly6Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with COG5-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0013	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	B;B;.
Vest4		0.26
MutPred		0.38		Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);
MVP		0.36
MPC		0.38
ClinPred		0.41	T
GERP RS		0.83
Varity_R		0.17
gMVP		0.090

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: rs772868659; hg19: chr7-107204418;