rs36059701

Variant names:

• chr4-4860018-C-G
• rs36059701
• NM_002448.3:c.119C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002448.3(MSX1):​c.119C>G​(p.Ala40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,500,962 control chromosomes in the GnomAD database, including 18,800 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1594 hom., cov: 33)
  • Exomes 𝑓: 0.16 (17206 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.761
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014262795).
• BP6: Variant 4-4860018-C-G is Benign according to our data. Variant chr4-4860018-C-G is described in ClinVar as Benign. ClinVar VariationId is 802050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.119C>G	p.Ala40Gly	missense_variant	Exon 1 of 2	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.119C>G	p.Ala40Gly	missense_variant	Exon 1 of 2	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1	n.304-3229G>C		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.49-3229G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21331 AN: 151922 Hom.: 1595 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.150 AC: 15047 AN: 100178 AF XY: 0.149

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0965

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0517

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.156 AC: 210803 AN: 1348932 Hom.: 17206 Cov.: 34 AF XY: 0.155 AC XY: 103375 AN XY: 665042

African (AFR) AF: 0.103 AC: 2794 AN: 27030

American (AMR) AF: 0.100 AC: 2906 AN: 28940

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4430 AN: 23482

East Asian (EAS) AF: 0.0618 AC: 1907 AN: 30852

South Asian (SAS) AF: 0.119 AC: 8738 AN: 73694

European-Finnish (FIN) AF: 0.209 AC: 9780 AN: 46712

Middle Eastern (MID) AF: 0.153 AC: 693 AN: 4536

European-Non Finnish (NFE) AF: 0.162 AC: 171398 AN: 1058082

Other (OTH) AF: 0.147 AC: 8157 AN: 55604

GnomAD4 genome AF: 0.140 AC: 21327 AN: 152030 Hom.: 1594 Cov.: 33 AF XY: 0.141 AC XY: 10501 AN XY: 74318

African (AFR) AF: 0.103 AC: 4261 AN: 41522

American (AMR) AF: 0.118 AC: 1800 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 678 AN: 3466

East Asian (EAS) AF: 0.0521 AC: 269 AN: 5166

South Asian (SAS) AF: 0.116 AC: 561 AN: 4830

European-Finnish (FIN) AF: 0.211 AC: 2225 AN: 10546

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.164 AC: 11121 AN: 67906

Other (OTH) AF: 0.128 AC: 270 AN: 2110

Alfa AF: 0.159 Hom.: 447

Bravo AF: 0.131

ESP6500AA AF: 0.0963 AC: 241

ESP6500EA AF: 0.141 AC: 677

ExAC AF: 0.106 AC: 2136

Asia WGS AF: 0.0850 AC: 291 AN: 3420

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28965043, 28204848, 16723652, 15379328, 21866112, 25565750, 21740177)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.76
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.30	N
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Vest4		0.061
ClinPred		0.0035	T
GERP RS		2.9
PromoterAI		-0.067	Neutral
Varity_R		0.058
gMVP		0.39
Mutation Taster		=96/4	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: rs36059701; hg19: chr4-4861745; COSMIC: COSV66947195; COSMIC: COSV66947195;