5-150379638-C-T

Variant names:

• chr5-150379638-C-T
• rs114689020
• NM_001371623.1:c.2765C>T

Variant summary

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

The NM_001371623.1(TCOF1):​c.2765C>T​(p.Ser922Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,614,150 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S922S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (100 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (108 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.491
• Publications: 6 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028220415).
• BP6: Variant 5-150379638-C-T is Benign according to our data. Variant chr5-150379638-C-T is described in ClinVar as Benign. ClinVar VariationId is 130570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.2765C>T	p.Ser922Leu	missense	Exon 17 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.2765C>T	p.Ser922Leu	missense	Exon 17 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.2765C>T	p.Ser922Leu	missense	Exon 17 of 26	NP_001128716.1	Q13428-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.2765C>T	p.Ser922Leu	missense	Exon 17 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.2765C>T	p.Ser922Leu	missense	Exon 17 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.2534C>T	p.Ser845Leu	missense	Exon 16 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3179 AN: 152174 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00685 AC: 1720 AN: 251162 AF XY: 0.00550

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00338 AC: 4939 AN: 1461858 Hom.: 108 Cov.: 31 AF XY: 0.00308 AC XY: 2237 AN XY: 727232

African (AFR) AF: 0.0713 AC: 2387 AN: 33480

American (AMR) AF: 0.00546 AC: 244 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86258

European-Finnish (FIN) AF: 0.00317 AC: 169 AN: 53384

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00144 AC: 1604 AN: 1112012

Other (OTH) AF: 0.00632 AC: 382 AN: 60396

GnomAD4 genome AF: 0.0209 AC: 3176 AN: 152292 Hom.: 100 Cov.: 32 AF XY: 0.0197 AC XY: 1467 AN XY: 74462

African (AFR) AF: 0.0685 AC: 2847 AN: 41552

American (AMR) AF: 0.00888 AC: 136 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68018

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00781 Hom.: 57

Bravo AF: 0.0235

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0638 AC: 281

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00872 AC: 1059

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.2
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.49
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.080
Sift	Uncertain	0.017	D
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.063
MVP		0.12
MPC		0.069
ClinPred		0.0037	T
GERP RS		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.050
gMVP		0.072
Mutation Taster		=95/5	polymorphism (auto)

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: rs114689020; hg19: chr5-149759201;