4-4862654-A-G

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
• Publications: 11 publications found

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]

MSX1 Gene-Disease associations (from GenCC):

• orofacial cleft 5

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• tooth agenesis, selective, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth and nail syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000308455 (HGNC:):

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 VariationId 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
ENSG00000308455	ENST00000834195.1	n.304-5865T>C		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.48+5009T>C		intron_variant	Intron 1 of 1

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

African (AFR) AF: 0.139 AC: 4628 AN: 33322

American (AMR) AF: 0.212 AC: 9486 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 6292 AN: 26100

East Asian (EAS) AF: 0.0588 AC: 2333 AN: 39660

South Asian (SAS) AF: 0.159 AC: 13705 AN: 86110

European-Finnish (FIN) AF: 0.252 AC: 11208 AN: 44420

Middle Eastern (MID) AF: 0.241 AC: 1386 AN: 5756

European-Non Finnish (NFE) AF: 0.236 AC: 261009 AN: 1105236

Other (OTH) 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

African (AFR) AF: 0.142 AC: 5874 AN: 41502

American (AMR) AF: 0.204 AC: 3114 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 848 AN: 3470

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5178

South Asian (SAS) AF: 0.150 AC: 723 AN: 4826

European-Finnish (FIN) AF: 0.261 AC: 2764 AN: 10600

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.234 AC: 15886 AN: 67984

Other (OTH) AF: 0.200 AC: 423 AN: 2110

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
PhyloP100		-0.63
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

Other links and lift over

dbSNP: rs1042484; hg19: chr4-4864381; COSMIC: COSV66947264;