chr1-165769074-A-T

Variant names:

• chr1-165769074-A-T
• rs2251768
• ENST00000580248.5:c.-182-805T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000580248.5(TMCO1):​c.-182-805T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 725,160 control chromosomes in the GnomAD database, including 286,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59358 hom., cov: 31)
  • Exomes 𝑓: 0.89 (226712 hom.)
• Consequence: TMCO1 ENST00000580248.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.43
• Publications: 13 publications found

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]

TMCO1-AS1 (HGNC:54046): (TMCO1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-165769074-A-T is Benign according to our data. Variant chr1-165769074-A-T is described in ClinVar as Benign. ClinVar VariationId is 1273808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000580248.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1-AS1	NR_125374.1		n.146A>T		non_coding_transcript_exon	Exon 1 of 3
	TMCO1	NM_019026.6	MANE Select	c.-323T>A		upstream_gene	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.-170T>A		upstream_gene	N/A	NP_001243093.1	B7Z591

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	ENST00000580248.5	TSL:2	c.-182-805T>A		intron	N/A	ENSP00000462588.1	J3QQY2
	TMCO1-AS1	ENST00000423121.1	TSL:2	n.146A>T		non_coding_transcript_exon	Exon 1 of 2
	TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.-323T>A		upstream_gene	N/A	ENSP00000356856.6	Q9UM00-1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134192 AN: 152052 Hom.: 59312 Cov.: 31

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.926

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.886

GnomAD4 exome AF: 0.888 AC: 509049 AN: 572990 Hom.: 226712 Cov.: 7 AF XY: 0.891 AC XY: 264711 AN XY: 297182

African (AFR) AF: 0.885 AC: 13110 AN: 14818

American (AMR) AF: 0.858 AC: 17531 AN: 20428

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 13574 AN: 14794

East Asian (EAS) AF: 0.996 AC: 31639 AN: 31752

South Asian (SAS) AF: 0.936 AC: 45707 AN: 48812

European-Finnish (FIN) AF: 0.815 AC: 24210 AN: 29694

Middle Eastern (MID) AF: 0.923 AC: 2037 AN: 2206

European-Non Finnish (NFE) AF: 0.879 AC: 334496 AN: 380386

Other (OTH) AF: 0.889 AC: 26745 AN: 30100

GnomAD4 genome AF: 0.883 AC: 134297 AN: 152170 Hom.: 59358 Cov.: 31 AF XY: 0.882 AC XY: 65643 AN XY: 74404

African (AFR) AF: 0.887 AC: 36811 AN: 41518

American (AMR) AF: 0.873 AC: 13357 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 3213 AN: 3470

East Asian (EAS) AF: 0.991 AC: 5115 AN: 5162

South Asian (SAS) AF: 0.938 AC: 4522 AN: 4820

European-Finnish (FIN) AF: 0.819 AC: 8671 AN: 10592

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.877 AC: 59630 AN: 67996

Other (OTH) AF: 0.887 AC: 1875 AN: 2114

Alfa AF: 0.843 Hom.: 2606

Bravo AF: 0.885

Asia WGS AF: 0.955 AC: 3320 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.14
DANN	Benign	0.59
PhyloP100		-2.4
PromoterAI		0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2251768; hg19: chr1-165738311;