Genetic Variant NM_005221.6:c.115G>C (chr7-97024509-C-G) – 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>C(p.Glu39Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DLX5
NM_005221.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.85

Publications

1 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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005221.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLX5	NM_005221.6	MANE Select	c.115G>C	p.Glu39Gln	missense	Exon 1 of 3	NP_005212.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLX5	ENST00000648378.1	MANE Select	c.115G>C	p.Glu39Gln	missense	Exon 1 of 3	ENSP00000498116.1
DLX5	ENST00000486603.2	TSL:2	c.115G>C	p.Glu39Gln	missense	Exon 1 of 2	ENSP00000475008.1
DLX5	ENST00000493764.1	TSL:5	n.319G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.0

PhyloP100

7.8

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.50

Sift

Benign

0.084

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.41

MutPred

0.17

Loss of glycosylation at P38 (P = 0.1691)

MVP

0.90

MPC

1.3

ClinPred

0.98

GERP RS

4.9

PromoterAI

-0.00080

Neutral

(source)

Varity_R

0.15

gMVP

0.48

Mutation Taster

=48/52

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over