rs75583421

Variant names:

• chr5-150375799-G-A
• rs75583421
• NM_001371623.1:c.1783G>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.1783G>A​(p.Val595Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,614,248 control chromosomes in the GnomAD database, including 102 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 34)
  • Exomes 𝑓: 0.0097 (92 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.390
• Publications: 10 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=0.005758971).
• BP6: Variant 5-150375799-G-A is Benign according to our data. Variant chr5-150375799-G-A is described in ClinVar as Benign. ClinVar VariationId is 352213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00784 (1194/152362) while in subpopulation NFE AF = 0.0111 (756/68028). AF 95% confidence interval is 0.0105. There are 10 homozygotes in GnomAd4. There are 603 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1194 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.1783G>A	p.Val595Ile	missense	Exon 12 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.1783G>A	p.Val595Ile	missense	Exon 12 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.1783G>A	p.Val595Ile	missense	Exon 12 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.1783G>A	p.Val595Ile	missense	Exon 12 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.1783G>A	p.Val595Ile	missense	Exon 12 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.1552G>A	p.Val518Ile	missense	Exon 11 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1194 AN: 152244 Hom.: 10 Cov.: 34

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00746 AC: 1875 AN: 251374 AF XY: 0.00741

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00973 AC: 14231 AN: 1461886 Hom.: 92 Cov.: 35 AF XY: 0.00960 AC XY: 6983 AN XY: 727242

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00318 AC: 142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00937 AC: 245 AN: 26136

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

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86258

European-Finnish (FIN) AF: 0.0135 AC: 720 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12481 AN: 1112010

Other (OTH) AF: 0.00808 AC: 488 AN: 60396

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152362 Hom.: 10 Cov.: 34 AF XY: 0.00809 AC XY: 603 AN XY: 74512

African (AFR) AF: 0.00207 AC: 86 AN: 41594

American (AMR) AF: 0.00725 AC: 111 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0111 AC: 756 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00943 Hom.: 16

Bravo AF: 0.00650

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00765 AC: 929

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00942

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.39
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.14
Sift	Uncertain	0.016	D
Sift4G	Benign	0.16	T
Polyphen		0.95	P
Vest4		0.11
MVP		0.43
MPC		0.38
ClinPred		0.020	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.047
Mutation Taster		=97/3	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: rs75583421; hg19: chr5-149755362; COSMIC: COSV99059926; COSMIC: COSV99059926;