rs1042484

Variant names:

• chr4-4862654-A-G
• rs1042484
• NM_002448.3:c.470-47A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002448.3(MSX1):​c.470-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,597,544 control chromosomes in the GnomAD database, including 40,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3176 hom., cov: 34)
  • Exomes 𝑓: 0.22 (37230 hom.)
• Consequence: MSX1 NM_002448.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.634

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-4862654-A-G is Benign according to our data. Variant chr4-4862654-A-G is described in ClinVar as [Benign]. Clinvar id is 1241303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.470-47A>G		intron_variant	Intron 1 of 1	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.470-47A>G		intron_variant	Intron 1 of 1	1	NM_002448.3	ENSP00000372170.4
MSX1	ENST00000468421.1	n.181+46A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30110 AN: 152052 Hom.: 3177 Cov.: 34

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.204 AC: 48045 AN: 235490 AF XY: 0.203

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.0468

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.223 AC: 322526 AN: 1445374 Hom.: 37230 Cov.: 30 AF XY: 0.222 AC XY: 159589 AN XY: 719978

Gnomad4 AFR exome AF: 0.139 AC: 4628 AN: 33322

Gnomad4 AMR exome AF: 0.212 AC: 9486 AN: 44712

Gnomad4 ASJ exome AF: 0.241 AC: 6292 AN: 26100

Gnomad4 EAS exome AF: 0.0588 AC: 2333 AN: 39660

Gnomad4 SAS exome AF: 0.159 AC: 13705 AN: 86110

Gnomad4 FIN exome AF: 0.252 AC: 11208 AN: 44420

Gnomad4 NFE exome AF: 0.236 AC: 261009 AN: 1105236

Gnomad4 Remaining exome AF: 0.208 AC: 12479 AN: 60058

GnomAD4 genome AF: 0.198 AC: 30118 AN: 152170 Hom.: 3176 Cov.: 34 AF XY: 0.198 AC XY: 14710 AN XY: 74408

Gnomad4 AFR AF: 0.142 AC: 0.141535 AN: 0.141535

Gnomad4 AMR AF: 0.204 AC: 0.203583 AN: 0.203583

Gnomad4 ASJ AF: 0.244 AC: 0.24438 AN: 0.24438

Gnomad4 EAS AF: 0.0512 AC: 0.0511781 AN: 0.0511781

Gnomad4 SAS AF: 0.150 AC: 0.149814 AN: 0.149814

Gnomad4 FIN AF: 0.261 AC: 0.260755 AN: 0.260755

Gnomad4 NFE AF: 0.234 AC: 0.233673 AN: 0.233673

Gnomad4 OTH AF: 0.200 AC: 0.200474 AN: 0.200474

Alfa AF: 0.224 Hom.: 5182

Bravo AF: 0.192

Asia WGS AF: 0.110 AC: 384 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.073
DANN	Benign	0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1042484; hg19: chr4-4864381; COSMIC: COSV66947264;