Genetic Variant NM_005221.6:c.115G>A (chr7-97024509-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005221.6(DLX5):c.115G>A(p.Glu39Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DLX5
NM_005221.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.85

Publications

0 publications found

Variant links:

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

DLX5 links:

ENSG00000296253 (HGNC:):

ENSG00000296253 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLX5	NM_005221.6 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 3	ENST00000648378.1	NP_005212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DLX5	ENST00000648378.1 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 3		NM_005221.6	ENSP00000498116.1
DLX5	ENST00000486603.2 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 2	2		ENSP00000475008.1
DLX5	ENST00000493764.1 link	n.319G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5
ENSG00000296253	ENST00000737642.1 link	n.110-2948C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

LIST_S2

Benign

0.0

.;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.0

M;M;M

PhyloP100

7.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.1

N;.;.

Sift

Benign

0.077

T;.;.

Sift4G

Benign

0.17

T;.;T

Vest4

0.59

ClinPred

0.99

GERP RS

4.9

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.17

gMVP

0.60

Mutation Taster

=40/60

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over