9-19332142-A-C

Variant names:

• chr9-19332142-A-C
• rs142191750
• NM_001330640.2:c.2418A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001330640.2(DENND4C):​c.2418A>C​(p.Val806Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,614,014 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0064 (51 hom.)
• Consequence: DENND4C NM_001330640.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.80
• Publications: 5 publications found

Genes affected

DENND4C (HGNC:26079): (DENN domain containing 4C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular response to insulin stimulus; protein localization to plasma membrane; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-19332142-A-C is Benign according to our data. Variant chr9-19332142-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2659105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2	c.2418A>C	p.Val806Val	synonymous_variant	Exon 17 of 33	ENST00000434457.7	NP_001317569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4C	ENST00000434457.7	c.2418A>C	p.Val806Val	synonymous_variant	Exon 17 of 33	5	NM_001330640.2	ENSP00000473469.1
DENND4C	ENST00000494124.2	n.*290-2835A>C		intron_variant	Intron 11 of 27	1		ENSP00000473273.1
DENND4C	ENST00000602925.5	c.2418A>C	p.Val806Val	synonymous_variant	Exon 17 of 32	5		ENSP00000473565.1
DENND4C	ENST00000380437.8	n.1736A>C		non_coding_transcript_exon_variant	Exon 13 of 29	5

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152180 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00731

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00450 AC: 1130 AN: 251332 AF XY: 0.00431

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00393

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00642 AC: 9388 AN: 1461716 Hom.: 51 Cov.: 31 AF XY: 0.00619 AC XY: 4503 AN XY: 727178

African (AFR) AF: 0.00114 AC: 38 AN: 33476

American (AMR) AF: 0.00125 AC: 56 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00436 AC: 233 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00789 AC: 8776 AN: 1111914

Other (OTH) AF: 0.00406 AC: 245 AN: 60388

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152298 Hom.: 2 Cov.: 31 AF XY: 0.00376 AC XY: 280 AN XY: 74466

African (AFR) AF: 0.00111 AC: 46 AN: 41578

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00731 AC: 497 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00595 Hom.: 0

Bravo AF: 0.00394

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DENND4C: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.99
DANN	Benign	0.76
PhyloP100		-1.8
Mutation Taster		=98/2	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: rs142191750; hg19: chr9-19332140;