rs1095

Variant names:

• chr4-4863211-C-A
• rs1095
• NM_002448.3:c.*68C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-4863211-C-A
• chr4-4863211-C-T

Variant summary

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

The NM_002448.3(MSX1):​c.*68C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MSX1 NM_002448.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.392
• Publications: 0 publications found

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]

MSX1 Gene-Disease associations (from GenCC):

• orofacial cleft 5

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• tooth agenesis, selective, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth and nail syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000308455 (HGNC:):

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 (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.*68C>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.*68C>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1	n.303+5597G>T		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.48+4452G>T		intron_variant	Intron 1 of 1
MSX1	ENST00000468421.1	n.*183C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338776 Hom.: 0 Cov.: 24 AF XY: 0.00000151 AC XY: 1 AN XY: 663854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31020

American (AMR) AF: 0.00 AC: 0 AN: 35910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24646

East Asian (EAS) AF: 0.00 AC: 0 AN: 36342

South Asian (SAS) AF: 0.00 AC: 0 AN: 78390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1037956

Other (OTH) AF: 0.00 AC: 0 AN: 56376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.1
DANN	Benign	0.88
PhyloP100		0.39

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: rs1095; hg19: chr4-4864938;