chr19-14388804-C-A

Variant names:

• chr19-14388804-C-A
• rs139113505
• NM_078481.4:c.176C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_078481.4(ADGRE5):​c.176C>A​(p.Thr59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.76
• Publications: 0 publications found

Genes affected

ADGRE5 (HGNC:1711): (adhesion G protein-coupled receptor E5) This gene encodes a member of the EGF-TM7 subfamily of adhesion G protein-coupled receptors, which mediate cell-cell interactions. These proteins are cleaved by self-catalytic proteolysis into a large extracellular subunit and seven-span transmembrane subunit, which associate at the cell surface as a receptor complex. The encoded protein may play a role in cell adhesion as well as leukocyte recruitment, activation and migration, and contains multiple extracellular EGF-like repeats which mediate binding to chondroitin sulfate and the cell surface complement regulatory protein CD55. Expression of this gene may play a role in the progression of several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms with 3 to 5 EGF-like repeats have been observed for this gene. This gene is found in a cluster with other EGF-TM7 genes on the short arm of chromosome 19. [provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09031376).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078481.4. 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
	ADGRE5	NM_078481.4	MANE Select	c.176C>A	p.Thr59Lys	missense	Exon 3 of 20	NP_510966.1	P48960-1
	ADGRE5	NM_001025160.3		c.176C>A	p.Thr59Lys	missense	Exon 3 of 19	NP_001020331.1	P48960-3
	ADGRE5	NM_001784.6		c.176C>A	p.Thr59Lys	missense	Exon 3 of 18	NP_001775.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRE5	ENST00000242786.6	TSL:1 MANE Select	c.176C>A	p.Thr59Lys	missense	Exon 3 of 20	ENSP00000242786.4	P48960-1
	ADGRE5	ENST00000357355.7	TSL:1	c.176C>A	p.Thr59Lys	missense	Exon 3 of 19	ENSP00000349918.2	P48960-3
	ADGRE5	ENST00000358600.7	TSL:1	c.176C>A	p.Thr59Lys	missense	Exon 3 of 18	ENSP00000351413.2	P48960-2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451284 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722230

African (AFR) AF: 0.00 AC: 0 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 44132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103748

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome Cov.: 28

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	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.0020
DANN	Benign	0.61
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.97	T
PhyloP100		-3.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.90	T
Sift4G	Benign	0.92	T
Vest4		0.22
MutPred		0.40		Gain of ubiquitination at T59 (P = 0.0117)
MVP		0.088
MPC		0.67
ClinPred		0.15	T
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.80
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139113505; hg19: chr19-14499616;