rs45491898

Variant names:

• chr5-150396792-G-C
• rs45491898
• NM_001371623.1:c.4295G>C

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.4295G>C​(p.Gly1432Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,610,616 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1432R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 31)
  • Exomes 𝑓: 0.022 (401 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.836
• Publications: 22 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=0.0030030906).
• BP6: Variant 5-150396792-G-C is Benign according to our data. Variant chr5-150396792-G-C is described in ClinVar as Benign. ClinVar VariationId is 130575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0178 (2711/152132) while in subpopulation AMR AF = 0.0294 (449/15278). AF 95% confidence interval is 0.0271. There are 43 homozygotes in GnomAd4. There are 1351 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2711 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.4295G>C	p.Gly1432Ala	missense	Exon 24 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.4292G>C	p.Gly1431Ala	missense	Exon 24 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.4181G>C	p.Gly1394Ala	missense	Exon 23 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.4295G>C	p.Gly1432Ala	missense	Exon 24 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.4292G>C	p.Gly1431Ala	missense	Exon 24 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.4061G>C	p.Gly1354Ala	missense	Exon 23 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2710 AN: 152014 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0185 AC: 4478 AN: 242024 AF XY: 0.0189

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0217 AC: 31697 AN: 1458484 Hom.: 401 Cov.: 33 AF XY: 0.0216 AC XY: 15635 AN XY: 725228

African (AFR) AF: 0.00409 AC: 137 AN: 33460

American (AMR) AF: 0.0213 AC: 943 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 872 AN: 26088

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.00830 AC: 712 AN: 85828

European-Finnish (FIN) AF: 0.0136 AC: 710 AN: 52296

Middle Eastern (MID) AF: 0.0270 AC: 155 AN: 5738

European-Non Finnish (NFE) AF: 0.0243 AC: 26958 AN: 1110854

Other (OTH) AF: 0.0200 AC: 1208 AN: 60302

GnomAD4 genome AF: 0.0178 AC: 2711 AN: 152132 Hom.: 43 Cov.: 31 AF XY: 0.0182 AC XY: 1351 AN XY: 74378

African (AFR) AF: 0.00417 AC: 173 AN: 41514

American (AMR) AF: 0.0294 AC: 449 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0113 AC: 120 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1687 AN: 67978

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.0242 Hom.: 10

Bravo AF: 0.0185

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0175 AC: 2120

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0030	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.84
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.19
Sift	Benign	0.042	D
Sift4G	Uncertain	0.047	D
Polyphen		0.41	B
Vest4		0.098
MPC		0.41
ClinPred		0.018	T
GERP RS		0.69
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.14
gMVP		0.0024
Mutation Taster		=99/1	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: rs45491898; hg19: chr5-149776355; COSMIC: COSV60347024; COSMIC: COSV60347024;