rs36059701

Positions:

• chr4-4860018-C-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:3
• Conservation: PhyloP100: -0.761

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 Benign. Variant got -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 id is 802050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-4860018-C-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MSX1	NM_002448.3	c.119C>G	p.Ala40Gly	missense_variant	1/2	ENST00000382723.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX1	ENST00000382723.5	c.119C>G	p.Ala40Gly	missense_variant	1/2	1	NM_002448.3	P1

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

GnomAD3 exomes AF: 0.150 AC: 15047 AN: 100178 Hom.: 1241 AF XY: 0.149 AC XY: 8314 AN XY: 55658

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 SAS exome AF: 0.125

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

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.0618

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.147

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

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.128

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

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
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.15
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Vest4		0.061
MPC		0.72
ClinPred		0.0035	T
GERP RS		2.9
Varity_R		0.058
gMVP		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

Publications

LitVar

Other links and lift over

dbSNP: rs36059701; hg19: chr4-4861745; COSMIC: COSV66947195; COSMIC: COSV66947195;