rs4838057

Variant names:

• chr9-123395081-A-C
• rs4838057
• NM_001352964.2:c.1632-7223T>G

Variant summary

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

The NM_001352964.2(DENND1A):​c.1632-7223T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,198 control chromosomes in the GnomAD database, including 1,940 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 0.15 (1940 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 1 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 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.1632-7223T>G		intron	N/A	NP_001339893.1
	DENND1A	NM_001393654.1		c.1578-7223T>G		intron	N/A	NP_001380583.1
	DENND1A	NM_001352965.2		c.1482-7223T>G		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.1632-7223T>G		intron	N/A	ENSP00000377763.4
	DENND1A	ENST00000473039.5	TSL:1	n.1441-7223T>G		intron	N/A
	DENND1A	ENST00000866226.1		c.1578-7223T>G		intron	N/A	ENSP00000536285.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22234 AN: 152080 Hom.: 1931 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.0968

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.146 AC: 22274 AN: 152198 Hom.: 1940 Cov.: 32 AF XY: 0.151 AC XY: 11207 AN XY: 74408

African (AFR) AF: 0.177 AC: 7363 AN: 41530

American (AMR) AF: 0.236 AC: 3601 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1187 AN: 5176

South Asian (SAS) AF: 0.263 AC: 1267 AN: 4820

European-Finnish (FIN) AF: 0.114 AC: 1208 AN: 10598

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.0968 AC: 6581 AN: 67996

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.120 Hom.: 2131

Bravo AF: 0.159

Asia WGS AF: 0.266 AC: 923 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.59
PhyloP100		-1.5
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: rs4838057; hg19: chr9-126157360;