rs7713638

Variant names:

• chr5-150379533-T-C
• rs7713638
• NM_001371623.1:c.2660T>C

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.2660T>C​(p.Val887Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,614,070 control chromosomes in the GnomAD database, including 21,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V887M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2669 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18336 hom.)
• Consequence: TCOF1 NM_001371623.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001368
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.97
• Publications: 33 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041772127).
• BP6: Variant 5-150379533-T-C is Benign according to our data. Variant chr5-150379533-T-C is described in ClinVar as Benign. ClinVar VariationId is 130569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.2660T>C	p.Val887Ala	missense splice_region	Exon 17 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.2660T>C	p.Val887Ala	missense splice_region	Exon 17 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.2660T>C	p.Val887Ala	missense splice_region	Exon 17 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.2660T>C	p.Val887Ala	missense splice_region	Exon 17 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.2660T>C	p.Val887Ala	missense splice_region	Exon 17 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.2429T>C	p.Val810Ala	missense splice_region	Exon 16 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27036 AN: 152088 Hom.: 2663 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.143 AC: 35997 AN: 251068 AF XY: 0.142

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0846

Gnomad ASJ exome AF: 0.0619

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.155 AC: 226007 AN: 1461864 Hom.: 18336 Cov.: 32 AF XY: 0.154 AC XY: 111784 AN XY: 727240

African (AFR) AF: 0.272 AC: 9107 AN: 33480

American (AMR) AF: 0.0875 AC: 3915 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1567 AN: 26136

East Asian (EAS) AF: 0.0899 AC: 3570 AN: 39700

South Asian (SAS) AF: 0.139 AC: 11962 AN: 86258

European-Finnish (FIN) AF: 0.138 AC: 7343 AN: 53396

Middle Eastern (MID) AF: 0.109 AC: 629 AN: 5768

European-Non Finnish (NFE) AF: 0.161 AC: 178642 AN: 1112008

Other (OTH) AF: 0.154 AC: 9272 AN: 60396

GnomAD4 genome AF: 0.178 AC: 27081 AN: 152206 Hom.: 2669 Cov.: 32 AF XY: 0.175 AC XY: 13019 AN XY: 74408

African (AFR) AF: 0.267 AC: 11086 AN: 41524

American (AMR) AF: 0.120 AC: 1838 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3472

East Asian (EAS) AF: 0.127 AC: 659 AN: 5176

South Asian (SAS) AF: 0.127 AC: 612 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1449 AN: 10598

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10778 AN: 67992

Other (OTH) AF: 0.160 AC: 339 AN: 2114

Alfa AF: 0.156 Hom.: 4996

Bravo AF: 0.179

TwinsUK AF: 0.159 AC: 588

ALSPAC AF: 0.159 AC: 614

ESP6500AA AF: 0.255 AC: 1125

ESP6500EA AF: 0.158 AC: 1362

ExAC AF: 0.146 AC: 17771

Asia WGS AF: 0.156 AC: 540 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.147

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0060
DANN	Benign	0.39
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PhyloP100		-4.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.12
Sift	Benign	0.62	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.093
ClinPred		0.0051	T
GERP RS		-7.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.016
gMVP		0.061
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.070		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: rs7713638; hg19: chr5-149759096; COSMIC: COSV60350852; COSMIC: COSV60350852;