9-123391357-G-A

Variant names:

• chr9-123391357-G-A
• rs1891641
• NM_001352964.2:c.1632-3499C>T

Variant summary

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

The NM_001352964.2(DENND1A):​c.1632-3499C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,178 control chromosomes in the GnomAD database, including 2,350 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 0.17 (2350 hom., cov: 33)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352964.2. 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
	DENND1A	NM_001352964.2	MANE Select	c.1632-3499C>T		intron	N/A	NP_001339893.1
	DENND1A	NM_001393654.1		c.1578-3499C>T		intron	N/A	NP_001380583.1
	DENND1A	NM_001352965.2		c.1482-3499C>T		intron	N/A	NP_001339894.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1A	ENST00000394215.7	TSL:5 MANE Select	c.1632-3499C>T		intron	N/A	ENSP00000377763.4
	DENND1A	ENST00000473039.5	TSL:1	n.1441-3499C>T		intron	N/A
	DENND1A	ENST00000373624.6	TSL:5	c.1578-7444C>T		intron	N/A	ENSP00000362727.2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25205 AN: 152060 Hom.: 2339 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.0963

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.166 AC: 25253 AN: 152178 Hom.: 2350 Cov.: 33 AF XY: 0.168 AC XY: 12518 AN XY: 74402

African (AFR) AF: 0.241 AC: 10008 AN: 41496

American (AMR) AF: 0.192 AC: 2930 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0717 AC: 249 AN: 3472

East Asian (EAS) AF: 0.0962 AC: 498 AN: 5178

South Asian (SAS) AF: 0.110 AC: 530 AN: 4828

European-Finnish (FIN) AF: 0.191 AC: 2020 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8490 AN: 67998

Other (OTH) AF: 0.163 AC: 344 AN: 2108

Alfa AF: 0.130 Hom.: 2629

Bravo AF: 0.170

Asia WGS AF: 0.0940 AC: 328 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.62
PhyloP100		-0.58
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: rs1891641; hg19: chr9-126153636;