chr20-62464881-C-G

Variant names:

• chr20-62464881-C-G
• rs148724629
• NM_080473.5:c.1149G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080473.5(GATA5):​c.1149G>C​(p.Arg383Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,458,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R383G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GATA5 NM_080473.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.910
• Publications: 0 publications found

Genes affected

GATA5 (HGNC:15802): (GATA binding protein 5) The protein encoded by this gene is a transcription factor that contains two GATA-type zinc fingers. The encoded protein is known to bind to hepatocyte nuclear factor-1alpha (HNF-1alpha), and this interaction is essential for cooperative activation of the intestinal lactase-phlorizin hydrolase promoter. In other organisms, similar proteins may be involved in the establishment of cardiac smooth muscle cell diversity. [provided by RefSeq, Jul 2008]

GATA5 Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types, 5

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02331525).
• BS2: High AC in GnomAdExome4 at 21 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080473.5. 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
	GATA5	NM_080473.5	MANE Select	c.1149G>C	p.Arg383Ser	missense	Exon 7 of 7	NP_536721.1	Q9BWX5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA5	ENST00000252997.3	TSL:1 MANE Select	c.1149G>C	p.Arg383Ser	missense	Exon 7 of 7	ENSP00000252997.2	Q9BWX5
	GATA5	ENST00000914293.1		c.1305G>C	p.Arg435Ser	missense	Exon 7 of 7	ENSP00000584352.1
	GATA5	ENST00000861188.1		c.1149G>C	p.Arg383Ser	missense	Exon 7 of 7	ENSP00000531247.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246700 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458262 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 725248

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.0000225 AC: 1 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5474

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110780

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.0010
DANN	Benign	0.19
DEOGEN2	Benign	0.10	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-0.91
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.21
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.36		Gain of glycosylation at R383 (P = 0.0073)
MVP		0.67
MPC		0.090
ClinPred		0.11	T
GERP RS		-11
Varity_R		0.086
gMVP		0.24
Mutation Taster		=91/9	polymorphism

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: rs148724629; hg19: chr20-61039937;