4-4863211-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002448.3(MSX1):​c.*68C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,491,052 control chromosomes in the GnomAD database, including 880 homozygotes. 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: 𝑓 0.017 (134 hom., cov: 32)
  • Exomes 𝑓: 0.012 (746 hom.)
• Consequence: MSX1 NM_002448.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.392
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002448.3. 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
	MSX1	NM_002448.3	MANE Select	c.*68C>T		3_prime_UTR	Exon 2 of 2	NP_002439.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.*68C>T		3_prime_UTR	Exon 2 of 2	ENSP00000372170.4
	ENSG00000308455	ENST00000834195.1		n.303+5597G>A		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.48+4452G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2581 AN: 152188 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.0122 AC: 16304 AN: 1338746 Hom.: 746 Cov.: 24 AF XY: 0.0122 AC XY: 8113 AN XY: 663844

African (AFR) AF: 0.00316 AC: 98 AN: 31020

American (AMR) AF: 0.124 AC: 4456 AN: 35904

Ashkenazi Jewish (ASJ) AF: 0.00848 AC: 209 AN: 24646

East Asian (EAS) AF: 0.126 AC: 4564 AN: 36336

South Asian (SAS) AF: 0.0230 AC: 1804 AN: 78386

European-Finnish (FIN) AF: 0.000381 AC: 13 AN: 34096

Middle Eastern (MID) AF: 0.00668 AC: 27 AN: 4040

European-Non Finnish (NFE) AF: 0.00392 AC: 4064 AN: 1037944

Other (OTH) AF: 0.0190 AC: 1069 AN: 56374

GnomAD4 genome AF: 0.0170 AC: 2595 AN: 152306 Hom.: 134 Cov.: 32 AF XY: 0.0186 AC XY: 1384 AN XY: 74466

African (AFR) AF: 0.00387 AC: 161 AN: 41584

American (AMR) AF: 0.0796 AC: 1218 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.129 AC: 663 AN: 5158

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00473 AC: 322 AN: 68030

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.00990 Hom.: 10

Bravo AF: 0.0236

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.8
DANN	Benign	0.89
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV107493071; COSMIC: COSV107493071;