rs1553878166

Positions:

• chr4-4862983-TC-AA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002448.3(MSX1):​c.752_753delinsAA​(p.Phe251Ter) 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 (★).

• 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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.175 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX1	NM_002448.3	c.752_753delinsAA	p.Phe251Ter	stop_gained	2/2	ENST00000382723.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX1	ENST00000382723.5	c.752_753delinsAA	p.Phe251Ter	stop_gained	2/2	1	NM_002448.3	P1
MSX1	ENST00000468421.1	n.464_465delinsAA		non_coding_transcript_exon_variant	2/2	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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2016

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. 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. 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. 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. -

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;