rs3783462

Positions:

• chr1-67685544-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001924.4(GADD45A):​c.44+6T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,604,954 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0067 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: GADD45A NM_001924.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.07474
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

Genes affected

GADD45A (HGNC:4095): (growth arrest and DNA damage inducible alpha) This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase. The DNA damage-induced transcription of this gene is mediated by both p53-dependent and -independent mechanisms. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00666 (1014/152194) while in subpopulation AFR AF= 0.0234 (972/41528). AF 95% confidence interval is 0.0222. There are 15 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1014 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GADD45A	NM_001924.4	c.44+6T>A		splice_donor_region_variant, intron_variant		ENST00000370986.9
GADD45A	NM_001199741.2	c.44+6T>A		splice_donor_region_variant, intron_variant
GADD45A	NM_001199742.2	c.44+6T>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GADD45A	ENST00000370986.9	c.44+6T>A		splice_donor_region_variant, intron_variant		1	NM_001924.4	P1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1010 AN: 152076 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00152 AC: 350 AN: 230962 Hom.: 4 AF XY: 0.00110 AC XY: 138 AN XY: 125200

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.000691

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.000691

GnomAD4 exome AF: 0.000632 AC: 918 AN: 1452760 Hom.: 8 Cov.: 31 AF XY: 0.000533 AC XY: 385 AN XY: 721788

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.000706

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000993

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00666 AC: 1014 AN: 152194 Hom.: 15 Cov.: 33 AF XY: 0.00629 AC XY: 468 AN XY: 74404

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00695

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.075
dbscSNV1_RF	Benign	0.25
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

Publications

LitVar

Other links and lift over

dbSNP: rs3783462; hg19: chr1-68151227;