4-4862983-TC-AA

Variant names:

• chr4-4862983-TC-AA
• rs1553878166
• NM_002448.3:c.752_753delTCinsAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002448.3(MSX1):​c.752_753delTCinsAA​(p.Phe251*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSX1 NM_002448.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

Genes affected

MSX1 (HGNC:7391): (msh homeobox 1) This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.752_753delTCinsAA	p.Phe251*	stop_gained		ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.752_753delTCinsAA	p.Phe251*	stop_gained		1	NM_002448.3	ENSP00000372170.4
MSX1	ENST00000468421.1	n.464_465delTCinsAA		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Uncertain:1

Oct 31, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the last exon of the MSX1 mRNA at codon 251 (p.Phe251*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 52 amino acids of the MSX1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSX1-related disease. An experimental study has shown that the the last 32 amino acids of the MSX1 protein are critical for DNA binding specificity, nuclear localization, and transcriptional repression (PMID: 16600910). However, the clinical significance of these effects on protein function is unknown. In summary, this is a novel truncating variant in the last exon of the MSX1 gene. While it is absent from the population and removes residues that may be important for protein function, the current evidence is insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553878166; hg19: chr4-4864710;