7-97020904-G-T

Position:

• chr7-97020904-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005221.6(DLX5):​c.702C>A​(p.Ser234Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,188 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0085 (12 hom., cov: 33)
  • Exomes 𝑓: 0.012 (114 hom.)
• Consequence: DLX5 NM_005221.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.94

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067386925).
• BP6: Variant 7-97020904-G-T is Benign according to our data. Variant chr7-97020904-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1212745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-97020904-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLX5	NM_005221.6	c.702C>A	p.Ser234Arg	missense_variant	3/3	ENST00000648378.1	NP_005212.1
DLX5	XM_005250185.4	c.318C>A	p.Ser106Arg	missense_variant	3/3		XP_005250242.1
DLX5	XM_017011803.2	c.318C>A	p.Ser106Arg	missense_variant	3/3		XP_016867292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLX5	ENST00000648378.1	c.702C>A	p.Ser234Arg	missense_variant	3/3		NM_005221.6	ENSP00000498116	P1
DLX5	ENST00000493764.1	n.824C>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1300 AN: 152252 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00791

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0100 AC: 2518 AN: 251206 Hom.: 22 AF XY: 0.0102 AC XY: 1382 AN XY: 135820

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00905

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0117 AC: 17147 AN: 1461818 Hom.: 114 Cov.: 31 AF XY: 0.0117 AC XY: 8501 AN XY: 727202

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00945

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00945

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00854 AC: 1301 AN: 152370 Hom.: 12 Cov.: 33 AF XY: 0.00891 AC XY: 664 AN XY: 74506

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00790

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00730 Hom.: 0

Bravo AF: 0.00750

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.0104 AC: 1259

EpiCase AF: 0.0133

EpiControl AF: 0.0125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DLX5: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	.;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.28
Sift	Benign	0.13	T;.
Sift4G	Benign	0.23	T;.
Polyphen		0.0050	B;B
Vest4		0.29
MutPred		0.12		Loss of phosphorylation at S234 (P = 0.0089);Loss of phosphorylation at S234 (P = 0.0089);
MPC		0.53
ClinPred		0.0071	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.53

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: rs35273378; hg19: chr7-96650216;