rs387906737

chr7-97022192-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_005221.6(DLX5):c.533A>C(p.Gln178Pro) variant causes a missense 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLX5 NM_005221.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.97

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 6 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity DLX5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_005221.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 7-97022192-T-G is Pathogenic according to our data. Variant chr7-97022192-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 30021.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-97022192-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLX5	NM_005221.6	c.533A>C	p.Gln178Pro	missense_variant	2/3	ENST00000648378.1
DLX5	XM_005250185.4	c.149A>C	p.Gln50Pro	missense_variant	2/3
DLX5	XM_017011803.2	c.149A>C	p.Gln50Pro	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLX5	ENST00000648378.1	c.533A>C	p.Gln178Pro	missense_variant	2/3		NM_005221.6	P1
DLX5	ENST00000486603.2	c.533A>C	p.Gln178Pro	missense_variant	2/2	2
DLX5	ENST00000493764.1	n.655A>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Split hand-foot malformation 1 with sensorineural hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	-0.58	N;N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D;.;.
REVEL	Pathogenic	0.81
Sift	Benign	0.052	T;.;.
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.52		Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);
MVP		0.97
MPC		0.56
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906737; hg19: chr7-96651504;