4-4860247-C-T

Variant names:

• chr4-4860247-C-T
• rs34165410
• NM_002448.3:c.348C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002448.3(MSX1):​c.348C>T​(p.Gly116Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,586,738 control chromosomes in the GnomAD database, including 3,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (358 hom., cov: 32)
  • Exomes 𝑓: 0.058 (3344 hom.)
• Consequence: MSX1 NM_002448.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.484
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 4-4860247-C-T is Benign according to our data. Variant chr4-4860247-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	NM_002448.3	MANE Select	c.348C>T	p.Gly116Gly	synonymous	Exon 1 of 2	NP_002439.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.348C>T	p.Gly116Gly	synonymous	Exon 1 of 2	ENSP00000372170.4
	ENSG00000308455	ENST00000834195.1		n.304-3458G>A		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-3458G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0634 AC: 9638 AN: 152040 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.0779

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0471

Gnomad OTH AF: 0.0727

GnomAD2 exomes AF: 0.0678 AC: 14096 AN: 208056 AF XY: 0.0725

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.0436

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.0691

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0628

GnomAD4 exome AF: 0.0578 AC: 82954 AN: 1434586 Hom.: 3344 Cov.: 36 AF XY: 0.0610 AC XY: 43529 AN XY: 713272

African (AFR) AF: 0.0857 AC: 2756 AN: 32158

American (AMR) AF: 0.0449 AC: 1965 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 1004 AN: 25582

East Asian (EAS) AF: 0.102 AC: 3974 AN: 38818

South Asian (SAS) AF: 0.170 AC: 14279 AN: 84192

European-Finnish (FIN) AF: 0.0438 AC: 1661 AN: 37928

Middle Eastern (MID) AF: 0.0535 AC: 304 AN: 5684

European-Non Finnish (NFE) AF: 0.0480 AC: 53143 AN: 1106670

Other (OTH) AF: 0.0647 AC: 3868 AN: 59756

GnomAD4 genome AF: 0.0634 AC: 9642 AN: 152152 Hom.: 358 Cov.: 32 AF XY: 0.0653 AC XY: 4860 AN XY: 74376

African (AFR) AF: 0.0831 AC: 3452 AN: 41524

American (AMR) AF: 0.0593 AC: 907 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.0782 AC: 402 AN: 5138

South Asian (SAS) AF: 0.166 AC: 800 AN: 4814

European-Finnish (FIN) AF: 0.0437 AC: 464 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0471 AC: 3200 AN: 67972

Other (OTH) AF: 0.0720 AC: 152 AN: 2112

Alfa AF: 0.0528 Hom.: 62

Bravo AF: 0.0635

Asia WGS AF: 0.157 AC: 545 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypoplastic enamel-onycholysis-hypohidrosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		0.48
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34165410; hg19: chr4-4861974; COSMIC: COSV66947305; COSMIC: COSV66947305;