rs574569798

Variant names:

• chr5-150396821-GAGA-G
• rs574569798
• NM_001371623.1:c.4332_4334delGAA

Your query was ambiguous. Multiple possible variants found:

• chr5-150396821-GAGA-G
• chr5-150396821-GAGA-GAGAAGA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):​c.4332_4334delGAA​(p.Lys1445del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00343 in 1,605,566 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: TCOF1 NM_001371623.1 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.69
• Publications: 3 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001371623.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-150396821-GAGA-G is Benign according to our data. Variant chr5-150396821-GAGA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352236.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 = 0.00322 (490/152156) while in subpopulation NFE AF = 0.0044 (299/68000). AF 95% confidence interval is 0.00399. There are 1 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 490 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.4332_4334delGAA	p.Lys1445del	disruptive_inframe_deletion	Exon 24 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.4329_4331delGAA	p.Lys1444del	disruptive_inframe_deletion	Exon 24 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.4218_4220delGAA	p.Lys1407del	disruptive_inframe_deletion	Exon 23 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.4332_4334delGAA	p.Lys1445del	disruptive_inframe_deletion	Exon 24 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.4329_4331delGAA	p.Lys1444del	disruptive_inframe_deletion	Exon 24 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.4098_4100delGAA	p.Lys1367del	disruptive_inframe_deletion	Exon 23 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152038 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00440

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00313 AC: 720 AN: 229938 AF XY: 0.00298

Gnomad AFR exome AF: 0.000292

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.0000577

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00346 AC: 5023 AN: 1453410 Hom.: 12 AF XY: 0.00336 AC XY: 2429 AN XY: 722212

African (AFR) AF: 0.000569 AC: 19 AN: 33414

American (AMR) AF: 0.00182 AC: 79 AN: 43428

Ashkenazi Jewish (ASJ) AF: 0.00135 AC: 35 AN: 25962

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39506

South Asian (SAS) AF: 0.000235 AC: 20 AN: 85060

European-Finnish (FIN) AF: 0.0112 AC: 579 AN: 51794

Middle Eastern (MID) AF: 0.000703 AC: 4 AN: 5686

European-Non Finnish (NFE) AF: 0.00372 AC: 4125 AN: 1108444

Other (OTH) AF: 0.00268 AC: 161 AN: 60116

GnomAD4 genome AF: 0.00322 AC: 490 AN: 152156 Hom.: 1 Cov.: 30 AF XY: 0.00363 AC XY: 270 AN XY: 74382

African (AFR) AF: 0.000650 AC: 27 AN: 41514

American (AMR) AF: 0.00203 AC: 31 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00440 AC: 299 AN: 68000

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00117 Hom.: 1

Bravo AF: 0.00237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs574569798; hg19: chr5-149776384; COSMIC: COSV60349133; COSMIC: COSV60349133;