chr1-165743318-G-A

Variant names:

• chr1-165743318-G-A
• rs200248108
• NM_019026.6:c.324-7C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_019026.6(TMCO1):​c.324-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (0 hom., cov: 28)
  • Exomes 𝑓: 0.035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001840
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.652

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-165743318-G-A is Benign according to our data. Variant chr1-165743318-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1156516.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-165743318-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCO1	NM_019026.6	c.324-7C>T		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000367881.11	NP_061899.3
TMCO1	NM_001256164.1	c.375-7C>T		splice_region_variant, intron_variant	Intron 5 of 6		NP_001243093.1
TMCO1	NM_001256165.1	c.288-7C>T		splice_region_variant, intron_variant	Intron 5 of 6		NP_001243094.1
TMCO1	NR_045818.1	n.418-7C>T		splice_region_variant, intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO1	ENST00000367881.11	c.324-7C>T		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_019026.6	ENSP00000356856.6

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 770 AN: 94310 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00958

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00817

Gnomad EAS AF: 0.00645

Gnomad SAS AF: 0.00338

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.00905

Gnomad OTH AF: 0.00544

GnomAD2 exomes AF: 0.240 AC: 36836 AN: 153726 AF XY: 0.243

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0352 AC: 43837 AN: 1247094 Hom.: 0 Cov.: 32 AF XY: 0.0403 AC XY: 25145 AN XY: 624102

Gnomad4 AFR exome AF: 0.0407 AC: 1129 AN: 27754

Gnomad4 AMR exome AF: 0.132 AC: 4839 AN: 36642

Gnomad4 ASJ exome AF: 0.0690 AC: 1576 AN: 22832

Gnomad4 EAS exome AF: 0.0420 AC: 1499 AN: 35684

Gnomad4 SAS exome AF: 0.0862 AC: 6409 AN: 74334

Gnomad4 FIN exome AF: 0.164 AC: 7830 AN: 47848

Gnomad4 NFE exome AF: 0.0198 AC: 18767 AN: 945670

Gnomad4 Remaining exome AF: 0.0293 AC: 1525 AN: 52006

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00818 AC: 772 AN: 94324 Hom.: 0 Cov.: 28 AF XY: 0.00964 AC XY: 436 AN XY: 45212

Gnomad4 AFR AF: 0.00530 AC: 0.00530021 AN: 0.00530021

Gnomad4 AMR AF: 0.00512 AC: 0.00512338 AN: 0.00512338

Gnomad4 ASJ AF: 0.00817 AC: 0.00817439 AN: 0.00817439

Gnomad4 EAS AF: 0.00678 AC: 0.00677757 AN: 0.00677757

Gnomad4 SAS AF: 0.00341 AC: 0.0034098 AN: 0.0034098

Gnomad4 FIN AF: 0.0231 AC: 0.0231012 AN: 0.0231012

Gnomad4 NFE AF: 0.00907 AC: 0.00907487 AN: 0.00907487

Gnomad4 OTH AF: 0.00541 AC: 0.00540958 AN: 0.00540958

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0914 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.7
DANN	Benign	0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
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: rs200248108; hg19: chr1-165712555; COSMIC: COSV63317692;