rs3783462

Variant names:

• chr1-67685544-T-A
• rs3783462
• NM_001924.4:c.44+6T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001924.4(GADD45A):​c.44+6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,604,954 control chromosomes in the GnomAD database, including 23 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: GADD45A NM_001924.4 splice_region, intron
• Scores: Splicing: ADA: 0.07474
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1014 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001924.4. 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
	GADD45A	NM_001924.4	MANE Select	c.44+6T>A		splice_region intron	N/A	NP_001915.1	P24522-1
	GADD45A	NM_001199741.2		c.44+6T>A		splice_region intron	N/A	NP_001186670.1	P24522-2
	GADD45A	NM_001199742.2		c.44+6T>A		splice_region intron	N/A	NP_001186671.1	A5JUZ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GADD45A	ENST00000370986.9	TSL:1 MANE Select	c.44+6T>A		splice_region intron	N/A	ENSP00000360025.4	P24522-1
	GADD45A	ENST00000617962.2	TSL:1	c.44+6T>A		splice_region intron	N/A	ENSP00000482814.2	A0A087WZQ0
	GADD45A	ENST00000370985.4	TSL:1	c.44+6T>A		splice_region intron	N/A	ENSP00000360024.3	P24522-2

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

GnomAD2 exomes AF: 0.00152 AC: 350 AN: 230962 AF XY: 0.00110

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 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

African (AFR) AF: 0.0239 AC: 796 AN: 33318

American (AMR) AF: 0.000706 AC: 31 AN: 43908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52426

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1107274

Other (OTH) AF: 0.00125 AC: 75 AN: 59982

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

African (AFR) AF: 0.0234 AC: 972 AN: 41528

American (AMR) AF: 0.00196 AC: 30 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67996

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.21
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3783462; hg19: chr1-68151227;