5-150374288-C-A

Variant names:

• chr5-150374288-C-A
• rs119470016
• NM_001371623.1:c.985C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001371623.1(TCOF1):​c.985C>A​(p.Gln329Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

Genes affected

TCOF1 (HGNC:11654): (treacle ribosome biogenesis factor 1) This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

TCOF1 Gene-Disease associations (from GenCC):

• Treacher Collins syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110305965).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371623.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.985C>A	p.Gln329Lys	missense	Exon 8 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.985C>A	p.Gln329Lys	missense	Exon 8 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.985C>A	p.Gln329Lys	missense	Exon 8 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.985C>A	p.Gln329Lys	missense	Exon 8 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.985C>A	p.Gln329Lys	missense	Exon 8 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.754C>A	p.Gln252Lys	missense	Exon 7 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149754 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1441810 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715492

African (AFR) AF: 0.00 AC: 0 AN: 32968

American (AMR) AF: 0.00 AC: 0 AN: 41902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 38782

South Asian (SAS) AF: 0.00 AC: 0 AN: 83842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101320

Other (OTH) AF: 0.00 AC: 0 AN: 59622

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149884 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73182

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

African (AFR) AF: 0.00 AC: 0 AN: 40798

American (AMR) AF: 0.00 AC: 0 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4860

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67270

Other (OTH) AF: 0.00 AC: 0 AN: 2060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.070
Sift	Uncertain	0.025	D
Sift4G	Benign	0.25	T
Polyphen		0.96	D
Vest4		0.25
MutPred		0.19		Gain of methylation at Q329 (P = 0.0073)
MVP		0.26
MPC		0.38
ClinPred		0.18	T
GERP RS		2.2
Varity_R		0.27
gMVP		0.033
Mutation Taster		=94/6	polymorphism

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: rs119470016; hg19: chr5-149753851;