rs73270846

Variant names:

• chr5-150376525-C-T
• rs73270846
• NM_001371623.1:c.2245C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-150376525-C-T
• chr5-150376525-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):​c.2245C>T​(p.Pro749Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,454 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (21 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.116
• Publications: 5 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=0.0032149255).
• BP6: Variant 5-150376525-C-T is Benign according to our data. Variant chr5-150376525-C-T is described in ClinVar as Benign. ClinVar VariationId is 130568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0091 (1386/152304) while in subpopulation AFR AF = 0.0303 (1259/41554). AF 95% confidence interval is 0.0289. There are 21 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1386 AD gene.

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.2245C>T	p.Pro749Ser	missense	Exon 14 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.2245C>T	p.Pro749Ser	missense	Exon 14 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.2245C>T	p.Pro749Ser	missense	Exon 14 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.2245C>T	p.Pro749Ser	missense	Exon 14 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.2245C>T	p.Pro749Ser	missense	Exon 14 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.2014C>T	p.Pro672Ser	missense	Exon 13 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.00909 AC: 1384 AN: 152186 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00242 AC: 591 AN: 243864 AF XY: 0.00170

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00106 AC: 1551 AN: 1459150 Hom.: 23 Cov.: 34 AF XY: 0.000938 AC XY: 681 AN XY: 725772

African (AFR) AF: 0.0314 AC: 1050 AN: 33400

American (AMR) AF: 0.00218 AC: 96 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00212 AC: 12 AN: 5654

European-Non Finnish (NFE) AF: 0.000225 AC: 250 AN: 1110764

Other (OTH) AF: 0.00232 AC: 140 AN: 60282

GnomAD4 genome AF: 0.00910 AC: 1386 AN: 152304 Hom.: 21 Cov.: 34 AF XY: 0.00846 AC XY: 630 AN XY: 74472

African (AFR) AF: 0.0303 AC: 1259 AN: 41554

American (AMR) AF: 0.00562 AC: 86 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00372 Hom.: 21

Bravo AF: 0.0108

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.12
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.27
Sift	Benign	0.080	T
Sift4G	Benign	0.54	T
Polyphen		0.49	P
Vest4		0.14
MVP		0.24
MPC		0.099
ClinPred		0.038	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.082
gMVP		0.11
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73270846; hg19: chr5-149756088;