7-97022208-A-C

Position:

• chr7-97022208-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005221.6(DLX5):​c.517T>G​(p.Ser173Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLX5 NM_005221.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLX5	NM_005221.6	c.517T>G	p.Ser173Ala	missense_variant	2/3	ENST00000648378.1
DLX5	XM_005250185.4	c.133T>G	p.Ser45Ala	missense_variant	2/3
DLX5	XM_017011803.2	c.133T>G	p.Ser45Ala	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLX5	ENST00000648378.1	c.517T>G	p.Ser173Ala	missense_variant	2/3		NM_005221.6	P1
DLX5	ENST00000486603.2	c.517T>G	p.Ser173Ala	missense_variant	2/2	2
DLX5	ENST00000493764.1	n.639T>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.517T>G (p.S173A) alteration is located in exon 2 (coding exon 2) of the DLX5 gene. This alteration results from a T to G substitution at nucleotide position 517, causing the serine (S) at amino acid position 173 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.085	N;N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.026	D;.;.
Sift4G	Uncertain	0.034	D;.;D
Polyphen		0.61	P;P;.
Vest4		0.56
MutPred		0.52		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.87
MPC		0.44
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.33

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: rs1790083169; hg19: chr7-96651520;