rs587777842

Variant names:

• chr7-97024509-C-A
• rs587777842
• NM_005221.6:c.115G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-97024509-C-A
• chr7-97024509-C-G
• chr7-97024509-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005221.6(DLX5):​c.115G>T​(p.Glu39*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLX5 NM_005221.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.85
• Publications: 1 publications found

Genes affected

DLX5 (HGNC:2918): (distal-less homeobox 5) This gene encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. The encoded protein may play a role in bone development and fracture healing. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation. [provided by RefSeq, Jul 2008]

DLX5 Gene-Disease associations (from GenCC):

• split hand-foot malformation 1 with sensorineural hearing loss

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• split hand-foot malformation 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296253 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-97024509-C-A is Pathogenic according to our data. Variant chr7-97024509-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156469.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLX5	NM_005221.6	c.115G>T	p.Glu39*	stop_gained	Exon 1 of 3	ENST00000648378.1	NP_005212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLX5	ENST00000648378.1	c.115G>T	p.Glu39*	stop_gained	Exon 1 of 3		NM_005221.6	ENSP00000498116.1
DLX5	ENST00000486603.2	c.115G>T	p.Glu39*	stop_gained	Exon 1 of 2	2		ENSP00000475008.1
DLX5	ENST00000493764.1	n.319G>T		non_coding_transcript_exon_variant	Exon 1 of 3	5
ENSG00000296253	ENST00000737642.1	n.110-2948C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Split hand-foot malformation 1 Pathogenic:1

Sep 05, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.8
Vest4		0.86
GERP RS		4.9
PromoterAI		-0.034	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs587777842; hg19: chr7-96653821;