4-4860002-G-A

Position:

• chr4-4860002-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002448.3(MSX1):​c.103G>A​(p.Ala35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,343,266 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20611438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSX1	NM_002448.3	c.103G>A	p.Ala35Thr	missense_variant	1/2	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.103G>A	p.Ala35Thr	missense_variant	1/2	1	NM_002448.3	ENSP00000372170.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1343266 Hom.: 0 Cov.: 31 AF XY: 0.00000302 AC XY: 2 AN XY: 661954

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: 0.0000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.47e-7

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.103G>A (p.A35T) alteration is located in exon 1 (coding exon 1) of the MSX1 gene. This alteration results from a G to A substitution at nucleotide position 103, causing the alanine (A) at amino acid position 35 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.20	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.16
Sift	Benign	0.33	T
Sift4G	Benign	0.58	T
Vest4		0.13
MVP		0.74
MPC		0.68
ClinPred		0.14	T
GERP RS		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.066
gMVP		0.30

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: rs1226714798; hg19: chr4-4861729;