1-197511754-T-C

Position:

• chr1-197511754-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195215.2(DENND1B):​c.1789A>G​(p.Met597Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,608,678 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.19

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]

DENND1B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004513949).
• BP6: Variant 1-197511754-T-C is Benign according to our data. Variant chr1-197511754-T-C is described in ClinVar as [Benign]. Clinvar id is 712344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00138 (209/151874) while in subpopulation EAS AF= 0.0275 (141/5136). AF 95% confidence interval is 0.0238. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND1B	NM_001195215.2	c.1789A>G	p.Met597Val	missense_variant	22/23	ENST00000620048.6	NP_001182144.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND1B	ENST00000620048.6	c.1789A>G	p.Met597Val	missense_variant	22/23	5	NM_001195215.2	ENSP00000479816.1
DENND1B	ENST00000294737.11	n.*477A>G		non_coding_transcript_exon_variant	19/20	2		ENSP00000294737.7
DENND1B	ENST00000294737.11	n.*477A>G		3_prime_UTR_variant	19/20	2		ENSP00000294737.7

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 151756 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0274

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00250 AC: 619 AN: 247750 Hom.: 8 AF XY: 0.00226 AC XY: 303 AN XY: 133924

Gnomad AFR exome AF: 0.000745

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0317

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000751 AC: 1094 AN: 1456804 Hom.: 11 Cov.: 30 AF XY: 0.000709 AC XY: 514 AN XY: 724622

Gnomad4 AFR exome AF: 0.000602

Gnomad4 AMR exome AF: 0.000271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0000937

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000550

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00138 AC: 209 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74232

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0275

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00145 Hom.: 3

Bravo AF: 0.00178

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000165

EpiControl AF: 0.000179

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	0.054
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.39	T
Vest4		0.33
MVP		0.56
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.24
gMVP		0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78578977; hg19: chr1-197480884; COSMIC: COSV54146192;