7-42048451-G-T

Variant names:

• chr7-42048451-G-T
• rs367979286
• NM_000168.6:c.679+40C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000168.6(GLI3):​c.679+40C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,312,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-42048451-G-T is Benign according to our data. Variant chr7-42048451-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 255447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00149 (226/151946) while in subpopulation NFE AF = 0.00228 (155/67974). AF 95% confidence interval is 0.00199. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.679+40C>A		intron_variant	Intron 5 of 14	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.679+40C>A		intron_variant	Intron 5 of 14	5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 227 AN: 151828 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00149 AC: 373 AN: 250496 AF XY: 0.00155

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00875

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00177 AC: 2053 AN: 1160394 Hom.: 1 Cov.: 16 AF XY: 0.00178 AC XY: 1057 AN XY: 592258

African (AFR) AF: 0.000399 AC: 11 AN: 27566

American (AMR) AF: 0.000316 AC: 14 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.00872 AC: 211 AN: 24188

East Asian (EAS) AF: 0.00 AC: 0 AN: 38352

South Asian (SAS) AF: 0.000237 AC: 19 AN: 80274

European-Finnish (FIN) AF: 0.00232 AC: 123 AN: 53126

Middle Eastern (MID) AF: 0.000489 AC: 2 AN: 4094

European-Non Finnish (NFE) AF: 0.00189 AC: 1582 AN: 837984

Other (OTH) AF: 0.00180 AC: 91 AN: 50464

GnomAD4 genome AF: 0.00149 AC: 226 AN: 151946 Hom.: 1 Cov.: 29 AF XY: 0.00128 AC XY: 95 AN XY: 74258

African (AFR) AF: 0.000459 AC: 19 AN: 41414

American (AMR) AF: 0.000131 AC: 2 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 67974

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00214 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.81
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367979286; hg19: chr7-42088050;