rs398122527

Variant names:

• chr7-97021048-C-A
• rs398122527
• NM_005221.6:c.558G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005221.6(DLX5):​c.558G>T​(p.Gln186His) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLX5 NM_005221.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.06
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 7-97021048-C-A is Pathogenic according to our data. Variant chr7-97021048-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91861.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.558G>T	p.Gln186His	missense_variant	Exon 3 of 3	ENST00000648378.1	NP_005212.1
DLX5	XM_005250185.4	c.174G>T	p.Gln58His	missense_variant	Exon 3 of 3		XP_005250242.1
DLX5	XM_017011803.2	c.174G>T	p.Gln58His	missense_variant	Exon 3 of 3		XP_016867292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLX5	ENST00000648378.1	c.558G>T	p.Gln186His	missense_variant	Exon 3 of 3		NM_005221.6	ENSP00000498116.1
DLX5	ENST00000493764.1	n.680G>T		non_coding_transcript_exon_variant	Exon 3 of 3	5
ENSG00000296253	ENST00000737642.1	n.109+199C>A		intron_variant	Intron 1 of 3
ENSG00000296253	ENST00000737644.1	n.320+199C>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Split hand-foot malformation 1 Pathogenic:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

-

Dept of Medical Genetics; Shandong University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		4.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.75		Loss of disorder (P = 0.0944);Loss of disorder (P = 0.0944);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs398122527; hg19: chr7-96650360;