9-123670169-T-C

Position:

• chr9-123670169-T-C

Variant summary

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

The NM_001352964.2(DENND1A):​c.453+1122A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,070 control chromosomes in the GnomAD database, including 20,798 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 0.49 (20798 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.742

Genes affected

DENND1A (HGNC:29324): (DENN domain containing 1A) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND1A	NM_001352964.2	c.453+1122A>G		intron_variant		ENST00000394215.7	NP_001339893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND1A	ENST00000394215.7	c.453+1122A>G		intron_variant		5	NM_001352964.2	ENSP00000377763	A2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74546 AN: 151952 Hom.: 20735 Cov.: 32

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.440

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 74678 AN: 152070 Hom.: 20798 Cov.: 32 AF XY: 0.492 AC XY: 36562 AN XY: 74316

Gnomad4 AFR AF: 0.767

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.447

Alfa AF: 0.497 Hom.: 3037

Bravo AF: 0.498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.6
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs1928482; hg19: chr9-126432448;