chr13-45465155-C-G

Variant names:

• chr13-45465155-C-G
• rs141222488
• NM_031431.4:c.119C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_031431.4(COG3):​c.119C>G​(p.Thr40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COG3 NM_031431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.504

Genes affected

COG3 (HGNC:18619): (component of oligomeric golgi complex 3) This gene encodes a component of the conserved oligomeric Golgi (COG) complex which is composed of eight different subunits and is required for normal Golgi morphology and localization. Defects in the COG complex result in multiple deficiencies in protein glycosylation. The protein encoded by this gene is involved in ER-Golgi transport.[provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_031431.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.045630693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG3	NM_031431.4	c.119C>G	p.Thr40Arg	missense_variant	Exon 1 of 23	ENST00000349995.10	NP_113619.3
COG3	XM_047430702.1	c.119C>G	p.Thr40Arg	missense_variant	Exon 1 of 19		XP_047286658.1
COG3	XR_007063702.1	n.217C>G		non_coding_transcript_exon_variant	Exon 1 of 14
COG3	XR_429222.5	n.217C>G		non_coding_transcript_exon_variant	Exon 1 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG3	ENST00000349995.10	c.119C>G	p.Thr40Arg	missense_variant	Exon 1 of 23	1	NM_031431.4	ENSP00000258654.8

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000156 AC: 38 AN: 243770 AF XY: 0.000203

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000278

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461226 Hom.: 0 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000134 AC: 6 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53036

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5736

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1111878

Other (OTH) AF: 0.000282 AC: 17 AN: 60332

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68036

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119C>G (p.T40R) alteration is located in exon 1 (coding exon 1) of the COG3 gene. This alteration results from a C to G substitution at nucleotide position 119, causing the threonine (T) at amino acid position 40 to be replaced by an arginine (R). 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	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0045	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		0.50
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.11	N;.
REVEL	Benign	0.13
Sift	Benign	0.64	T;.
Sift4G	Benign	0.52	T;T
Polyphen		0.0060	B;B
Vest4		0.27
MVP		0.61
MPC		0.30
ClinPred		0.046	T
GERP RS		3.1
PromoterAI		-0.0042	Neutral
Varity_R		0.23
gMVP		0.55
Mutation Taster		=72/28	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

Publications

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Other links and lift over

dbSNP: rs141222488; hg19: chr13-46039290;