4-4860958-G-C

Variant names:

• chr4-4860958-G-C
• rs3116581
• NM_002448.3:c.469+590G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002448.3(MSX1):​c.469+590G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,084 control chromosomes in the GnomAD database, including 15,826 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15826 hom., cov: 33)
• Consequence: MSX1 NM_002448.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.759
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.469+590G>C		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.469+590G>C		intron_variant	Intron 1 of 1	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1	n.304-4169C>G		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.49-4169C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66396 AN: 151966 Hom.: 15785 Cov.: 33

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.426

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 66501 AN: 152084 Hom.: 15826 Cov.: 33 AF XY: 0.446 AC XY: 33129 AN XY: 74354

African (AFR) AF: 0.577 AC: 23949 AN: 41520

American (AMR) AF: 0.523 AC: 7994 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3518 AN: 5160

South Asian (SAS) AF: 0.433 AC: 2089 AN: 4820

European-Finnish (FIN) AF: 0.413 AC: 4362 AN: 10564

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22388 AN: 67954

Other (OTH) AF: 0.432 AC: 910 AN: 2108

Alfa AF: 0.392 Hom.: 1555

Bravo AF: 0.450

Asia WGS AF: 0.582 AC: 2021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		0.76
Mutation Taster		=100/0	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: rs3116581; hg19: chr4-4862685;