1-165743318-GAAAAAAA-GAAA

Variant names:

• chr1-165743318-GAAAA-G
• rs751227407
• NM_019026.6:c.324-11_324-8delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019026.6(TMCO1):​c.324-11_324-8delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,252,252 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: TMCO1 NM_019026.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• Publications: 0 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 Gene-Disease associations (from GenCC):

• cerebrofaciothoracic dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Laboratory for Molecular Medicine, Orphanet
• craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019026.6. 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	NM_019026.6	MANE Select	c.324-11_324-8delTTTT		splice_region intron	N/A	NP_061899.3	Q9UM00-1
	TMCO1	NM_001256164.1		c.375-11_375-8delTTTT		splice_region intron	N/A	NP_001243093.1	B7Z591
	TMCO1	NM_001256165.1		c.288-11_288-8delTTTT		splice_region intron	N/A	NP_001243094.1	B7Z591

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.324-11_324-8delTTTT		splice_region intron	N/A	ENSP00000356856.6	Q9UM00-1
	TMCO1	ENST00000612311.4	TSL:1	c.477-11_477-8delTTTT		splice_region intron	N/A	ENSP00000480514.1	Q9UM00-3
	TMCO1	ENST00000868463.1		c.447-11_447-8delTTTT		splice_region intron	N/A	ENSP00000538522.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000639 AC: 8 AN: 1252252 Hom.: 0 AF XY: 0.00000638 AC XY: 4 AN XY: 626910

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27886

American (AMR) AF: 0.00 AC: 0 AN: 37082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22982

East Asian (EAS) AF: 0.00 AC: 0 AN: 35856

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75178

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.00000527 AC: 5 AN: 948562

Other (OTH) AF: 0.0000191 AC: 1 AN: 52252

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

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

Other links and lift over

dbSNP: rs751227407; hg19: chr1-165712555;