rs1414674827

Positions:

• chr4-4859988-G-A
• chr4-4859988-G-C
• chr4-4859988-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_002448.3(MSX1):​c.89G>A​(p.Gly30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000597 in 1,340,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39773577).
• BP6: Variant 4-4859988-G-A is Benign according to our data. Variant chr4-4859988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 931187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX1	NM_002448.3	c.89G>A	p.Gly30Asp	missense_variant	1/2	ENST00000382723.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX1	ENST00000382723.5	c.89G>A	p.Gly30Asp	missense_variant	1/2	1	NM_002448.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000106 AC: 1 AN: 94474 Hom.: 0 AF XY: 0.0000191 AC XY: 1 AN XY: 52378

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: 0.0000309

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000597 AC: 8 AN: 1340592 Hom.: 0 Cov.: 30 AF XY: 0.00000908 AC XY: 6 AN XY: 660530

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000759

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 02, 2020

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BP4,BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.96	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T
Sift4G	Uncertain	0.023	D
Vest4		0.34
MVP		0.87
MPC		1.1
ClinPred		0.27	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.089
gMVP		0.46

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: rs1414674827; hg19: chr4-4861715;