19-14397699-T-A

Variant names:

• chr19-14397699-T-A
• NM_078481.4:c.667T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_078481.4(ADGRE5):​c.667T>A​(p.Ser223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.841

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRE5	NM_078481.4	c.667T>A	p.Ser223Thr	missense_variant	Exon 7 of 20	ENST00000242786.6	NP_510966.1
ADGRE5	NM_001025160.3	c.520T>A	p.Ser174Thr	missense_variant	Exon 6 of 19		NP_001020331.1
ADGRE5	NM_001784.6	c.388T>A	p.Ser130Thr	missense_variant	Exon 5 of 18		NP_001775.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRE5	ENST00000242786.6	c.667T>A	p.Ser223Thr	missense_variant	Exon 7 of 20	1	NM_078481.4	ENSP00000242786.4

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667T>A (p.S223T) alteration is located in exon 7 (coding exon 7) of the ADGRE5 gene. This alteration results from a T to A substitution at nucleotide position 667, causing the serine (S) at amino acid position 223 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	0.19
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.33	.;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.63	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;.;T;T
Sift4G	Benign	0.18	T;T;T;T
Vest4		0.25
MutPred		0.86		.;.;.;Loss of sheet (P = 0.1158);
MVP		0.57
MPC		2.0
ClinPred		0.17	T
GERP RS		1.4
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-14508511;