19-14638285-G-C

Position:

• chr19-14638285-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032571.5(ADGRE3):​c.1304C>G​(p.Thr435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADGRE3 NM_032571.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

Genes affected

ADGRE3 (HGNC:23647): (adhesion G protein-coupled receptor E3) This gene encodes a member of the class B seven-span transmembrane (TM7) receptor family expressed predominantly by cells of the immune system. Family members are characterized by an extended extracellular region with a variable number of N-terminal epidermal growth factor (EGF)-like domains coupled to a TM7 domain via a mucin-like spacer domain. This gene is closely linked to the gene encoding egf-like molecule containing mucin-like hormone receptor 2 on chromosome 19. This protein may play a role in myeloid-myeloid interactions during immune and inflammatory responses. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4190973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRE3	NM_032571.5	c.1304C>G	p.Thr435Ser	missense_variant	11/16	ENST00000253673.6	NP_115960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRE3	ENST00000253673.6	c.1304C>G	p.Thr435Ser	missense_variant	11/16	1	NM_032571.5	ENSP00000253673	P1
ADGRE3	ENST00000344373.8	c.1148C>G	p.Thr383Ser	missense_variant	10/15	1		ENSP00000340758
ADGRE3	ENST00000443157.6	c.926C>G	p.Thr309Ser	missense_variant	8/13	2		ENSP00000396208
ADGRE3	ENST00000599900.5	c.659C>G	p.Thr220Ser	missense_variant	10/15	5		ENSP00000471853

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

May 27, 2022

The c.1304C>G (p.T435S) alteration is located in exon 11 (coding exon 11) of the ADGRE3 gene. This alteration results from a C to G substitution at nucleotide position 1304, causing the threonine (T) at amino acid position 435 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	.;.;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Benign	0.092
Sift	Benign	0.42	T;T;.;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	D;D;.;P
Vest4		0.17
MutPred		0.50		.;.;.;Loss of glycosylation at T435 (P = 0.4379);
MVP		0.44
MPC		0.47
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.16

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: chr19-14749097;