1-197617713-T-A

Variant names:

• chr1-197617713-T-A
• rs371820117
• NM_001195215.2:c.719A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001195215.2(DENND1B):​c.719A>T​(p.Tyr240Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,607,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94
• Publications: 1 publications found

Genes affected

DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15145507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195215.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1B	NM_001195215.2	MANE Select	c.719A>T	p.Tyr240Phe	missense	Exon 11 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.719A>T	p.Tyr240Phe	missense	Exon 11 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.629A>T	p.Tyr210Phe	missense	Exon 11 of 16	NP_001287787.1	Q6P3S1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.719A>T	p.Tyr240Phe	missense	Exon 11 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.719A>T	p.Tyr240Phe	missense	Exon 11 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.629A>T	p.Tyr210Phe	missense	Exon 11 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 26 AN: 151164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000297

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000161 AC: 40 AN: 247894 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000350 AC: 510 AN: 1456496 Hom.: 0 Cov.: 30 AF XY: 0.000344 AC XY: 249 AN XY: 724690

African (AFR) AF: 0.0000302 AC: 1 AN: 33132

American (AMR) AF: 0.0000899 AC: 4 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.000421 AC: 466 AN: 1108196

Other (OTH) AF: 0.000650 AC: 39 AN: 59976

GnomAD4 genome AF: 0.000172 AC: 26 AN: 151164 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 73792

African (AFR) AF: 0.0000727 AC: 3 AN: 41290

American (AMR) AF: 0.000198 AC: 3 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000297 AC: 20 AN: 67424

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.95
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.065
Sift	Benign	0.30	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.32
MVP		0.093
MPC		0.044
ClinPred		0.059	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.39
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371820117; hg19: chr1-197586843;