7-97006051-G-GGCA

Variant names:

• chr7-97006051-G-GGCA
• rs530625473
• NM_005222.4:c.96_98dupGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_005222.4(DLX6):​c.96_98dupGCA​(p.Gln33dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,582,026 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q33Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 29)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: DLX6 NM_005222.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 2.11

Genes affected

DLX6 (HGNC:2919): (distal-less homeobox 6) This gene encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. This family is comprised of at least 6 different members that encode proteins with roles in forebrain and craniofacial development. This gene is in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7. [provided by RefSeq, Jul 2008]

DLX6-AS1 (HGNC:37151): (DLX6 antisense RNA 1) Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005222.4
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLX6	NM_005222.4	c.96_98dupGCA	p.Gln33dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000518156.3	NP_005213.3
DLX6-AS1	NR_015448.1	n.141+7871_141+7873dupTGC		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLX6	ENST00000518156.3	c.96_98dupGCA	p.Gln33dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_005222.4	ENSP00000428480.2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 309 AN: 150048 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00199

Gnomad ASJ AF: 0.000870

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.0000993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000594

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.000849 AC: 161 AN: 189612 AF XY: 0.000785

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000223

Gnomad EAS exome AF: 0.000591

Gnomad FIN exome AF: 0.000176

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000893 AC: 1279 AN: 1431882 Hom.: 1 Cov.: 34 AF XY: 0.000887 AC XY: 630 AN XY: 710042

Gnomad4 AFR exome AF: 0.00422 AC: 138 AN: 32734

Gnomad4 AMR exome AF: 0.00117 AC: 48 AN: 41156

Gnomad4 ASJ exome AF: 0.000156 AC: 4 AN: 25640

Gnomad4 EAS exome AF: 0.000706 AC: 27 AN: 38222

Gnomad4 SAS exome AF: 0.00142 AC: 116 AN: 81952

Gnomad4 FIN exome AF: 0.000420 AC: 21 AN: 49984

Gnomad4 NFE exome AF: 0.000779 AC: 855 AN: 1097310

Gnomad4 Remaining exome AF: 0.000980 AC: 58 AN: 59166

GnomAD4 genome AF: 0.00205 AC: 308 AN: 150144 Hom.: 2 Cov.: 29 AF XY: 0.00183 AC XY: 134 AN XY: 73326

Gnomad4 AFR AF: 0.00543 AC: 0.00543028 AN: 0.00543028

Gnomad4 AMR AF: 0.00199 AC: 0.00198623 AN: 0.00198623

Gnomad4 ASJ AF: 0.000870 AC: 0.000869565 AN: 0.000869565

Gnomad4 EAS AF: 0.000395 AC: 0.000395413 AN: 0.000395413

Gnomad4 SAS AF: 0.00126 AC: 0.00126103 AN: 0.00126103

Gnomad4 FIN AF: 0.0000993 AC: 0.0000993443 AN: 0.0000993443

Gnomad4 NFE AF: 0.000594 AC: 0.000593718 AN: 0.000593718

Gnomad4 OTH AF: 0.00145 AC: 0.00144648 AN: 0.00144648

Alfa AF: 0.000255 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.96_98dup, results in the insertion of 1 amino acid(s) of the DLX6 protein (p.Gln44dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DLX6-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

DLX6-related disorder Benign:1

Oct 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=54/46	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs530625473; hg19: chr7-96635363; COSMIC: COSV50295348; COSMIC: COSV50295348;