7-97021048-C-A

Position:

• chr7-97021048-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q186R) has been classified as Pathogenic.

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-97021049-T-C is described in Lovd as [Pathogenic].
• 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 id is 91861.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLX5	NM_005221.6	c.558G>T	p.Gln186His	missense_variant	3/3	ENST00000648378.1	NP_005212.1
DLX5	XM_005250185.4	c.174G>T	p.Gln58His	missense_variant	3/3		XP_005250242.1
DLX5	XM_017011803.2	c.174G>T	p.Gln58His	missense_variant	3/3		XP_016867292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLX5	ENST00000648378.1	c.558G>T	p.Gln186His	missense_variant	3/3		NM_005221.6	ENSP00000498116	P1
DLX5	ENST00000493764.1	n.680G>T		non_coding_transcript_exon_variant	3/3	5

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Dept of Medical Genetics; Shandong University

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- -

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
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122527; hg19: chr7-96650360;