rs12337273

Variant names:

• chr9-123804666-A-G
• rs12337273
• NM_001352964.2:c.89-12036T>C

Variant summary

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

The NM_001352964.2(DENND1A):​c.89-12036T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.072 in 152,228 control chromosomes in the GnomAD database, including 580 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 0.072 (580 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND1A	NM_001352964.2	c.89-12036T>C		intron_variant	Intron 2 of 23	ENST00000394215.7	NP_001339893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND1A	ENST00000394215.7	c.89-12036T>C		intron_variant	Intron 2 of 23	5	NM_001352964.2	ENSP00000377763.4
DENND1A	ENST00000373620.7	c.89-12036T>C		intron_variant	Intron 2 of 20	1		ENSP00000362722.3
DENND1A	ENST00000373618.1	c.43-12036T>C		intron_variant	Intron 2 of 18	1		ENSP00000362720.1
DENND1A	ENST00000373624.6	c.89-12036T>C		intron_variant	Intron 2 of 21	5		ENSP00000362727.2

Frequencies

GnomAD3 genomes AF: 0.0720 AC: 10953 AN: 152110 Hom.: 579 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0690

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

GnomAD4 genome AF: 0.0720 AC: 10963 AN: 152228 Hom.: 580 Cov.: 32 AF XY: 0.0730 AC XY: 5435 AN XY: 74438

African (AFR) AF: 0.151 AC: 6285 AN: 41502

American (AMR) AF: 0.0506 AC: 774 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5184

South Asian (SAS) AF: 0.0665 AC: 321 AN: 4826

European-Finnish (FIN) AF: 0.0556 AC: 590 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0360 AC: 2449 AN: 68024

Other (OTH) AF: 0.0682 AC: 144 AN: 2110

Alfa AF: 0.0635 Hom.: 57

Bravo AF: 0.0757

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.8
DANN	Benign	0.65
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs12337273; hg19: chr9-126566945;