1-165752181-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_019026.6(TMCO1):c.256-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,606,824 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (63 hom.)
• Consequence: TMCO1 NM_019026.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004043
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.697

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-165752181-C-T is Benign according to our data. Variant chr1-165752181-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1198076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO1	NM_019026.6	c.256-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367881.11
TMCO1	NM_001256164.1	c.307-12G>A		splice_polypyrimidine_tract_variant, intron_variant
TMCO1	NM_001256165.1	c.220-12G>A		splice_polypyrimidine_tract_variant, intron_variant
TMCO1	NR_045818.1	n.350-12G>A		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.256-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_019026.6	P1

Frequencies

GnomAD3 genomes AF: 0.00554 AC: 831 AN: 150114 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00222

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.00999

Gnomad OTH AF: 0.00242

GnomAD3 exomes AF: 0.00534 AC: 1339 AN: 250562 Hom.: 6 AF XY: 0.00537 AC XY: 728 AN XY: 135442

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.00407

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00865

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00811 AC: 11818 AN: 1456654 Hom.: 63 Cov.: 30 AF XY: 0.00794 AC XY: 5754 AN XY: 724900

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.000455

Gnomad4 SAS exome AF: 0.00477

Gnomad4 FIN exome AF: 0.00332

Gnomad4 NFE exome AF: 0.00959

Gnomad4 OTH exome AF: 0.00661

GnomAD4 genome AF: 0.00552 AC: 829 AN: 150170 Hom.: 6 Cov.: 31 AF XY: 0.00511 AC XY: 374 AN XY: 73162

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00259

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000979

Gnomad4 SAS AF: 0.00293

Gnomad4 FIN AF: 0.00222

Gnomad4 NFE AF: 0.00997

Gnomad4 OTH AF: 0.00240

Alfa AF: 0.00731 Hom.: 1

Bravo AF: 0.00531

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	7.6
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
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: rs145104339; hg19: chr1-165721418;