4-4860001-C-A

Variant names:

• chr4-4860001-C-A
• rs1349964186
• NM_002448.3:c.102C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002448.3(MSX1):​c.102C>A​(p.Ser34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,343,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S34G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• 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: Labcorp Genetics (formerly Invitae), ClinGen
• tooth agenesis

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

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

ENSG00000308455 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20615745).

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.102C>A	p.Ser34Arg	missense	Exon 1 of 2	NP_002439.2	P28360

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.102C>A	p.Ser34Arg	missense	Exon 1 of 2	ENSP00000372170.4	P28360
	ENSG00000308455	ENST00000834195.1		n.304-3212G>T		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-3212G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343404 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 662028

African (AFR) AF: 0.00 AC: 0 AN: 26850

American (AMR) AF: 0.00 AC: 0 AN: 27988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23080

East Asian (EAS) AF: 0.00 AC: 0 AN: 30712

South Asian (SAS) AF: 0.0000276 AC: 2 AN: 72470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4320

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055838

Other (OTH) AF: 0.00 AC: 0 AN: 55308

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.55
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.014
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.29
Sift	Benign	0.53	T
Sift4G	Benign	0.56	T
Vest4		0.41
MVP		0.36
MPC		0.78
ClinPred		0.050	T
GERP RS		0.61
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.059
gMVP		0.44
Mutation Taster		=95/5	polymorphism

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: rs1349964186; hg19: chr4-4861728; COSMIC: COSV66947116; COSMIC: COSV66947116;