1-153941294-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000361217.9(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 ENST00000361217.9 splice_region, intron
• Scores: Splicing: ADA: 0.0001426
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168
• Publications: 31 publications found

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]

DENND4B Gene-Disease associations (from GenCC):

• isolated cleft palate

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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361217.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND4B	NM_014856.3	MANE Select	c.1123-5T>C		splice_region intron	N/A	NP_055671.2
	DENND4B	NM_001367466.1		c.1156-5T>C		splice_region intron	N/A	NP_001354395.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND4B	ENST00000361217.9	TSL:1 MANE Select	c.1123-5T>C		splice_region intron	N/A	ENSP00000354597.4
	DENND4B	ENST00000368646.6	TSL:5	c.1156-5T>C		splice_region intron	N/A	ENSP00000357635.2
	DENND4B	ENST00000483561.2	TSL:4	n.444-5T>C		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.585 AC: 145571 AN: 248696 AF XY: 0.578

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 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

African (AFR) AF: 0.724 AC: 24224 AN: 33478

American (AMR) AF: 0.701 AC: 31326 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 11257 AN: 26134

East Asian (EAS) AF: 0.946 AC: 37545 AN: 39696

South Asian (SAS) AF: 0.631 AC: 54409 AN: 86244

European-Finnish (FIN) AF: 0.549 AC: 29299 AN: 53378

Middle Eastern (MID) AF: 0.542 AC: 3120 AN: 5758

European-Non Finnish (NFE) AF: 0.480 AC: 534155 AN: 1111706

Other (OTH) AF: 0.546 AC: 32969 AN: 60362

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

African (AFR) AF: 0.711 AC: 29442 AN: 41400

American (AMR) AF: 0.651 AC: 9952 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1481 AN: 3470

East Asian (EAS) AF: 0.942 AC: 4865 AN: 5164

South Asian (SAS) AF: 0.659 AC: 3173 AN: 4818

European-Finnish (FIN) AF: 0.559 AC: 5906 AN: 10560

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32202 AN: 67936

Other (OTH) AF: 0.561 AC: 1184 AN: 2112

Alfa AF: 0.544 Hom.: 29650

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.17
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2252508; hg19: chr1-153913770;