rs112039991

Variant names:

• chr5-150374653-G-A
• rs112039991
• NM_001371623.1:c.1120G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-150374653-G-A
• chr5-150374653-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001371623.1(TCOF1):​c.1120G>A​(p.Ala374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A374S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• 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: Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05591449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.1120G>A	p.Ala374Thr	missense_variant	Exon 9 of 27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.1120G>A	p.Ala374Thr	missense_variant	Exon 9 of 27		NM_001371623.1	ENSP00000493815.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.41
DEOGEN2	Benign	0.075	.;T;.;.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.85	T;T;T;T;.;T;T;T;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	.;M;.;.;M;.;.;M;M;M;M;M;.
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	.;N;N;N;.;.;.;.;N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.11	.;T;T;D;.;.;.;.;T;T;T;T;T
Sift4G	Benign	0.45	.;T;T;T;.;.;.;.;T;T;T;T;T
Polyphen		0.053, 0.043, 0.026, 0.074	.;B;B;B;.;.;.;.;B;B;B;B;.
Vest4		0.14, 0.15, 0.16, 0.17, 0.13, 0.17
MutPred		0.17		.;Gain of glycosylation at A374 (P = 0.0036);.;.;Gain of glycosylation at A374 (P = 0.0036);.;Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);
MVP		0.31
MPC		0.12
ClinPred		0.11	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.018
gMVP		0.020
Mutation Taster		=88/12	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: rs112039991; hg19: chr5-149754216;