1-165752165-C-G

Variant summary

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

The NM_019026.6(TMCO1):c.260G>C(p.Arg87Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 151,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TMCO1 NM_019026.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

Genes affected

TMCO1 (HGNC:18188): (transmembrane and coiled-coil domains 1) This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

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, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO1	NM_019026.6	c.260G>C	p.Arg87Pro	missense_variant	5/7	ENST00000367881.11
TMCO1	NM_001256164.1	c.311G>C	p.Arg104Pro	missense_variant	5/7
TMCO1	NM_001256165.1	c.224G>C	p.Arg75Pro	missense_variant	5/7
TMCO1	NR_045818.1	n.354G>C		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO1	ENST00000367881.11	c.260G>C	p.Arg87Pro	missense_variant	5/7	1	NM_019026.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151210 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151210 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73736

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000481

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TMCO1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 138 of the TMCO1 protein (p.Arg138Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.0040	D;D;D;D;D;.
Polyphen		0.89	.;P;.;.;.;.
Vest4		0.96
MutPred		0.67		.;Loss of MoRF binding (P = 0.002);.;.;.;.;
MVP		0.21
MPC		1.6
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.98

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: rs763875549; hg19: chr1-165721402;