rs3764962

Variant names:

• chr18-22183050-A-G
• rs3764962
• NM_005257.6:c.1620+7A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-22183050-A-G
• chr18-22183050-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005257.6(GATA6):​c.1620+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,597,168 control chromosomes in the GnomAD database, including 16,033 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (8361 hom., cov: 32)
  • Exomes 𝑓: 0.033 (7672 hom.)
• Consequence: GATA6 NM_005257.6 splice_region, intron
• Scores: Splicing: ADA: 0.0004652
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48
• Publications: 11 publications found

Genes affected

GATA6 (HGNC:4174): (GATA binding protein 6) This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]

GATA6 Gene-Disease associations (from GenCC):

• atrial septal defect 9

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tetralogy of fallot

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• conotruncal heart malformations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 18-22183050-A-G is Benign according to our data. Variant chr18-22183050-A-G is described in ClinVar as Benign. ClinVar VariationId is 129133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005257.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	NM_005257.6	MANE Select	c.1620+7A>G		splice_region intron	N/A	NP_005248.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	ENST00000269216.10	TSL:1 MANE Select	c.1620+7A>G		splice_region intron	N/A	ENSP00000269216.3
	GATA6	ENST00000581694.1	TSL:1	c.1620+7A>G		splice_region intron	N/A	ENSP00000462313.1
	GATA6	ENST00000853536.1		c.1728+7A>G		splice_region intron	N/A	ENSP00000523595.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29177 AN: 152026 Hom.: 8319 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.0303

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.0690 AC: 17332 AN: 251094 AF XY: 0.0556

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0537

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0329 AC: 47574 AN: 1445024 Hom.: 7672 Cov.: 29 AF XY: 0.0307 AC XY: 22088 AN XY: 720064

African (AFR) AF: 0.642 AC: 21277 AN: 33146

American (AMR) AF: 0.0809 AC: 3615 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 419 AN: 26032

East Asian (EAS) AF: 0.0612 AC: 2423 AN: 39584

South Asian (SAS) AF: 0.0311 AC: 2669 AN: 85904

European-Finnish (FIN) AF: 0.0173 AC: 926 AN: 53404

Middle Eastern (MID) AF: 0.0772 AC: 444 AN: 5754

European-Non Finnish (NFE) AF: 0.0111 AC: 12125 AN: 1096640

Other (OTH) AF: 0.0614 AC: 3676 AN: 59856

GnomAD4 genome AF: 0.192 AC: 29277 AN: 152144 Hom.: 8361 Cov.: 32 AF XY: 0.187 AC XY: 13939 AN XY: 74388

African (AFR) AF: 0.624 AC: 25859 AN: 41432

American (AMR) AF: 0.100 AC: 1531 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.0505 AC: 262 AN: 5184

South Asian (SAS) AF: 0.0303 AC: 146 AN: 4822

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10612

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 860 AN: 68014

Other (OTH) AF: 0.145 AC: 305 AN: 2108

Alfa AF: 0.0643 Hom.: 4008

Bravo AF: 0.219

Asia WGS AF: 0.0870 AC: 303 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0164

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Atrioventricular septal defect 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.068
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: rs3764962; hg19: chr18-19763011; COSMIC: COSV52524497; COSMIC: COSV52524497;