rs149960650

chr4-4862792-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002448.3(MSX1):c.561G>A(p.Leu187=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,613,562 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (44 hom.)
• Consequence: MSX1 NM_002448.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-4862792-G-A is Benign according to our data. Variant chr4-4862792-G-A is described in ClinVar as [Benign]. Clinvar id is 461601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-4862792-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00496 (755/152362) while in subpopulation NFE AF= 0.00747 (508/68038). AF 95% confidence interval is 0.00693. There are 1 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 755 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX1	NM_002448.3	c.561G>A	p.Leu187=	synonymous_variant	2/2	ENST00000382723.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX1	ENST00000382723.5	c.561G>A	p.Leu187=	synonymous_variant	2/2	1	NM_002448.3	P1
MSX1	ENST00000468421.1	n.273G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00219

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00468 AC: 1168 AN: 249414 Hom.: 7 AF XY: 0.00471 AC XY: 638 AN XY: 135426

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.00705

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00752 AC: 10983 AN: 1461200 Hom.: 44 Cov.: 34 AF XY: 0.00726 AC XY: 5280 AN XY: 726920

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00880

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74502

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00747

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00631 Hom.: 1

Bravo AF: 0.00508

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00682

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

MSX1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.4
Dann	Benign	0.97

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: rs149960650; hg19: chr4-4864519; COSMIC: COSV101235675;