rs4075

Variant names:

• chr4-4862299-G-T
• rs4075
• NM_002448.3:c.470-402G>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.470-402G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 367,588 control chromosomes in the GnomAD database, including 17,996 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 0.30 (7687 hom., cov: 34)
  • Exomes 𝑓: 0.29 (10309 hom.)
• Consequence: MSX1 NM_002448.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.445
• Publications: 10 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.470-402G>T		intron_variant	Intron 1 of 1	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.470-402G>T		intron_variant	Intron 1 of 1	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1	n.304-5510C>A		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.48+5364C>A		intron_variant	Intron 1 of 1
MSX1	ENST00000468421.1	n.-129G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46071 AN: 152066 Hom.: 7673 Cov.: 34

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.294 AC: 63327 AN: 215404 Hom.: 10309 AF XY: 0.291 AC XY: 33829 AN XY: 116118

African (AFR) AF: 0.244 AC: 1540 AN: 6324

American (AMR) AF: 0.464 AC: 4387 AN: 9448

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 1145 AN: 5552

East Asian (EAS) AF: 0.598 AC: 5514 AN: 9222

South Asian (SAS) AF: 0.259 AC: 9736 AN: 37644

European-Finnish (FIN) AF: 0.370 AC: 3652 AN: 9868

Middle Eastern (MID) AF: 0.244 AC: 361 AN: 1482

European-Non Finnish (NFE) AF: 0.271 AC: 33808 AN: 124764

Other (OTH) AF: 0.287 AC: 3184 AN: 11100

GnomAD4 genome AF: 0.303 AC: 46122 AN: 152184 Hom.: 7687 Cov.: 34 AF XY: 0.312 AC XY: 23227 AN XY: 74400

African (AFR) AF: 0.258 AC: 10703 AN: 41536

American (AMR) AF: 0.433 AC: 6628 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 737 AN: 3472

East Asian (EAS) AF: 0.605 AC: 3123 AN: 5158

South Asian (SAS) AF: 0.280 AC: 1348 AN: 4820

European-Finnish (FIN) AF: 0.370 AC: 3917 AN: 10588

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18779 AN: 68000

Other (OTH) AF: 0.295 AC: 623 AN: 2112

Alfa AF: 0.283 Hom.: 1267

Bravo AF: 0.305

Asia WGS AF: 0.409 AC: 1420 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.0
DANN	Benign	0.89
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4075; hg19: chr4-4864026; COSMIC: COSV66947278; COSMIC: COSV66947278;