7-41960988-A-AT

Variant names:

• chr7-41960988-A-AT
• rs138425063
• NM_000168.6:c.*3341dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000168.6(GLI3):​c.*3341dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 151,934 control chromosomes in the GnomAD database, including 1,527 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1523 hom., cov: 30)
  • Exomes 𝑓: 0.16 (4 hom.)
• Consequence: GLI3 NM_000168.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.849
• Publications: 1 publications found

Genes affected

GLI3 (HGNC:4319): (GLI family zinc finger 3) This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI3 Gene-Disease associations (from GenCC):

• Greig cephalopolysyndactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Pallister-Hall syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
• polydactyly, postaxial, type A1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• polysyndactyly 4

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• tibial hemimelia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acrocallosal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-41960988-A-AT is Benign according to our data. Variant chr7-41960988-A-AT is described in ClinVar as [Benign]. Clinvar id is 360156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.*3341dupA		3_prime_UTR_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.*3341dupA		3_prime_UTR_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3
GLI3	ENST00000677605.1	c.*3341dupA		3_prime_UTR_variant	Exon 15 of 15			ENSP00000503743.1
GLI3	ENST00000678429.1	c.*3341dupA		3_prime_UTR_variant	Exon 15 of 15			ENSP00000502957.1
GLI3	ENST00000677288.1	c.*3341dupA		3_prime_UTR_variant	Exon 14 of 14			ENSP00000503986.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18577 AN: 151382 Hom.: 1521 Cov.: 30

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.0734

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.162 AC: 70 AN: 432 Hom.: 4 Cov.: 0 AF XY: 0.173 AC XY: 45 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.164 AC: 70 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.123 AC: 18572 AN: 151502 Hom.: 1523 Cov.: 30 AF XY: 0.122 AC XY: 9062 AN XY: 74004

African (AFR) AF: 0.0328 AC: 1356 AN: 41322

American (AMR) AF: 0.0734 AC: 1115 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3468

East Asian (EAS) AF: 0.0673 AC: 345 AN: 5128

South Asian (SAS) AF: 0.189 AC: 906 AN: 4786

European-Finnish (FIN) AF: 0.191 AC: 2000 AN: 10446

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11967 AN: 67854

Other (OTH) AF: 0.102 AC: 214 AN: 2098

Alfa AF: 0.0419 Hom.: 54

Bravo AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Greig cephalopolysyndactyly syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polydactyly Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pallister-Hall syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs138425063; hg19: chr7-42000586; COSMIC: COSV67886193; COSMIC: COSV67886193;