15-65676526-A-T

Position:

• chr15-65676526-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001320835.1(DENND4A):​c.4288T>A​(p.Ser1430Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,798 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: DENND4A NM_001320835.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

Genes affected

DENND4A (HGNC:24321): (DENN domain containing 4A) This gene encodes a DENN domain-containing protein that may function as a guanine nucleotide exchange factor that specifically activates ras-related protein Rab-10. This protein also contains a interferon stimulated response element-binding domain and may be involved in regulating the v-myc avian myelocytomatosis viral (MYC) oncogene. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037634492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4A	NM_001320835.1	c.4288T>A	p.Ser1430Thr	missense_variant	24/33	ENST00000443035.8	NP_001307764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND4A	ENST00000443035.8	c.4288T>A	p.Ser1430Thr	missense_variant	24/33	1	NM_001320835.1	ENSP00000391167	A1
DENND4A	ENST00000431932.6	c.4156T>A	p.Ser1386Thr	missense_variant	23/32	1		ENSP00000396830	P3
DENND4A	ENST00000635620.2	c.4285T>A	p.Ser1429Thr	missense_variant	23/33	5		ENSP00000489304	A1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000277 AC: 69 AN: 249018 Hom.: 0 AF XY: 0.000267 AC XY: 36 AN XY: 135078

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000213 AC: 312 AN: 1461504 Hom.: 0 Cov.: 30 AF XY: 0.000210 AC XY: 153 AN XY: 727020

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.4285T>A (p.S1429T) alteration is located in exon 24 (coding exon 22) of the DENND4A gene. This alteration results from a T to A substitution at nucleotide position 4285, causing the serine (S) at amino acid position 1429 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.017	.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;.
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.070	N;N;.
REVEL	Benign	0.082
Sift	Benign	0.67	T;T;.
Sift4G	Benign	0.69	T;T;T
Polyphen		0.094	.;B;.
Vest4		0.096
MVP		0.45
MPC		0.083
ClinPred		0.043	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368132872; hg19: chr15-65968864;