1-153941294-A-G

Variant names:

• chr1-153941294-A-G
• rs2252508
• NM_014856.3:c.1123-5T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014856.3(DENND4B):​c.1123-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,414 control chromosomes in the GnomAD database, including 231,295 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (27167 hom., cov: 31)
  • Exomes 𝑓: 0.52 (204128 hom.)
• Consequence: DENND4B NM_014856.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001426
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168

Genes affected

DENND4B (HGNC:29044): (DENN domain containing 4B) Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4B	NM_014856.3	c.1123-5T>C		splice_region_variant, intron_variant	Intron 7 of 27	ENST00000361217.9	NP_055671.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4B	ENST00000361217.9	c.1123-5T>C		splice_region_variant, intron_variant	Intron 7 of 27	1	NM_014856.3	ENSP00000354597.4
DENND4B	ENST00000368646.6	c.1156-5T>C		splice_region_variant, intron_variant	Intron 7 of 21	5		ENSP00000357635.2
DENND4B	ENST00000483561.2	n.444-5T>C		splice_region_variant, intron_variant	Intron 2 of 2	4
DENND4B	ENST00000494683.1	n.62-5T>C		splice_region_variant, intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88720 AN: 151842 Hom.: 27120 Cov.: 31

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.563

GnomAD3 exomes AF: 0.585 AC: 145571 AN: 248696 Hom.: 45059 AF XY: 0.578 AC XY: 78009 AN XY: 134938

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.704

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.942

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.519 AC: 758304 AN: 1461454 Hom.: 204128 Cov.: 63 AF XY: 0.520 AC XY: 378105 AN XY: 726994

Gnomad4 AFR exome AF: 0.724

Gnomad4 AMR exome AF: 0.701

Gnomad4 ASJ exome AF: 0.431

Gnomad4 EAS exome AF: 0.946

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.546

GnomAD4 genome AF: 0.585 AC: 88823 AN: 151960 Hom.: 27167 Cov.: 31 AF XY: 0.594 AC XY: 44107 AN XY: 74282

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.651

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.659

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.561

Alfa AF: 0.515 Hom.: 12912

Bravo AF: 0.601

Asia WGS AF: 0.768 AC: 2670 AN: 3478

EpiCase AF: 0.495

EpiControl AF: 0.488

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.10		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: rs2252508; hg19: chr1-153913770;