1-165743318-G-A

Position:

• chr1-165743318-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_019026.6(TMCO1):​c.324-7C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, 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

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
TMCO1	NM_019026.6	c.324-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367881.11
TMCO1	NM_001256164.1	c.375-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TMCO1	NM_001256165.1	c.288-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TMCO1	NR_045818.1	n.418-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO1	ENST00000367881.11	c.324-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_019026.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 770 AN: 94310 Hom.: 0 Cov.: 28 FAILED QC

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

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

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0690

Gnomad4 EAS exome AF: 0.0420

Gnomad4 SAS exome AF: 0.0862

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0293

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

Gnomad4 AMR AF: 0.00512

Gnomad4 ASJ AF: 0.00817

Gnomad4 EAS AF: 0.00678

Gnomad4 SAS AF: 0.00341

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.00907

Gnomad4 OTH AF: 0.00541

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

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 14, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.7
DANN	Benign	0.35

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;