19-14388804-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_078481.4(ADGRE5):​c.176C>T​(p.Thr59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,589,410 control chromosomes in the GnomAD database, including 903 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T59K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (150 hom., cov: 28)
  • Exomes 𝑓: 0.016 (753 hom.)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.76
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027876496).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0879 is higher than 0.05.

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>T	p.Thr59Met	missense	Exon 3 of 20	NP_510966.1	P48960-1
	ADGRE5	NM_001025160.3		c.176C>T	p.Thr59Met	missense	Exon 3 of 19	NP_001020331.1	P48960-3
	ADGRE5	NM_001784.6		c.176C>T	p.Thr59Met	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>T	p.Thr59Met	missense	Exon 3 of 20	ENSP00000242786.4	P48960-1
	ADGRE5	ENST00000357355.7	TSL:1	c.176C>T	p.Thr59Met	missense	Exon 3 of 19	ENSP00000349918.2	P48960-3
	ADGRE5	ENST00000358600.7	TSL:1	c.176C>T	p.Thr59Met	missense	Exon 3 of 18	ENSP00000351413.2	P48960-2

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4931 AN: 151912 Hom.: 148 Cov.: 28

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0400

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0341

GnomAD2 exomes AF: 0.0136 AC: 3296 AN: 243212 AF XY: 0.0117

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0159 AC: 22800 AN: 1437380 Hom.: 753 Cov.: 32 AF XY: 0.0162 AC XY: 11594 AN XY: 715466

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0184 AC: 604 AN: 32738

American (AMR) AF: 0.113 AC: 4791 AN: 42214

Ashkenazi Jewish (ASJ) AF: 0.00917 AC: 238 AN: 25948

East Asian (EAS) AF: 0.0241 AC: 954 AN: 39542

South Asian (SAS) AF: 0.0290 AC: 2456 AN: 84614

European-Finnish (FIN) AF: 0.0243 AC: 1287 AN: 52952

Middle Eastern (MID) AF: 0.0181 AC: 103 AN: 5706

European-Non Finnish (NFE) AF: 0.0104 AC: 11332 AN: 1094152

Other (OTH) AF: 0.0174 AC: 1035 AN: 59514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0326 AC: 4949 AN: 152030 Hom.: 150 Cov.: 28 AF XY: 0.0341 AC XY: 2536 AN XY: 74296

African (AFR) AF: 0.0294 AC: 1220 AN: 41490

American (AMR) AF: 0.0919 AC: 1401 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 116 AN: 5134

South Asian (SAS) AF: 0.0406 AC: 196 AN: 4824

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10590

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1482 AN: 67974

Other (OTH) AF: 0.0337 AC: 71 AN: 2104

Alfa AF: 0.0177 Hom.: 40

Bravo AF: 0.0373

ExAC AF: 0.0250 AC: 3041

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.0080
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.071	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Vest4		0.13
MPC		0.51
ClinPred		0.015	T
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs139113505; hg19: chr19-14499616; COSMIC: COSV54411460;