19-2477825-T-G

Variant names:

• chr19-2477825-T-G
• rs14384
• NM_015675.4:c.*224T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015675.4(GADD45B):​c.*224T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 231,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GADD45B NM_015675.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.449
• Publications: 0 publications found

Genes affected

GADD45B (HGNC:4096): (growth arrest and DNA damage inducible beta) 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 genes in this group respond to environmental stresses by mediating activation of the p38/JNK pathway. This activation is mediated via their proteins binding and activating MTK1/MEKK4 kinase, which is an upstream activator of both p38 and JNK MAPKs. The function of these genes or their protein products is involved in the regulation of growth and apoptosis. These genes are regulated by different mechanisms, but they are often coordinately expressed and can function cooperatively in inhibiting cell growth. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GADD45B	NM_015675.4	c.*224T>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000215631.9	NP_056490.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GADD45B	ENST00000215631.9	c.*224T>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_015675.4	ENSP00000215631.3
GADD45B	ENST00000592937.1	n.1573T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
GADD45B	ENST00000718317.1	c.*196T>G		3_prime_UTR_variant	Exon 3 of 3			ENSP00000520751.1
GADD45B	ENST00000585359.1	n.*522T>G		downstream_gene_variant		3		ENSP00000466414.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000433 AC: 1 AN: 231048 Hom.: 0 Cov.: 0 AF XY: 0.00000811 AC XY: 1 AN XY: 123272

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6998

American (AMR) AF: 0.00 AC: 0 AN: 10692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7050

East Asian (EAS) AF: 0.00 AC: 0 AN: 12076

South Asian (SAS) AF: 0.00 AC: 0 AN: 33854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 966

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 135272

Other (OTH) AF: 0.0000773 AC: 1 AN: 12934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.75
PhyloP100		0.45

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: rs14384; hg19: chr19-2477823;