NM_002448.3:c.77G>A

Variant names:

• chr4-4859976-G-A
• rs567549350
• NM_002448.3:c.77G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002448.3(MSX1):​c.77G>A​(p.Gly26Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000449 in 1,336,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G26A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2733068).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.77G>A	p.Gly26Glu	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.77G>A	p.Gly26Glu	missense_variant	Exon 1 of 2	1	NM_002448.3	ENSP00000372170.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000111 AC: 1 AN: 89896 Hom.: 0 AF XY: 0.0000200 AC XY: 1 AN XY: 49932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000449 AC: 6 AN: 1336454 Hom.: 0 Cov.: 30 AF XY: 0.00000911 AC XY: 6 AN XY: 658438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.00094	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.31
Sift	Benign	0.25	T
Sift4G	Benign	0.70	T
Vest4		0.22
MVP		0.97
MPC		1.2
ClinPred		0.12	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.085
gMVP		0.41

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: rs567549350; hg19: chr4-4861703;