NM_001387552.1:c.675G>A

Variant names:

• chr4-61732830-G-A
• rs191915391
• NM_001387552.1:c.675G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001387552.1(ADGRL3):​c.675G>A​(p.Ala225Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,611,820 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (28 hom.)
• Consequence: ADGRL3 NM_001387552.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.220
• Publications: 1 publications found

Genes affected

ADGRL3 (HGNC:20974): (adhesion G protein-coupled receptor L3) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-61732830-G-A is Benign according to our data. Variant chr4-61732830-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2654778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00366 (5336/1459596) while in subpopulation MID AF = 0.0194 (112/5766). AF 95% confidence interval is 0.0165. There are 28 homozygotes in GnomAdExome4. There are 2807 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 406 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387552.1. 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
	ADGRL3	NM_001387552.1	MANE Select	c.675G>A	p.Ala225Ala	synonymous	Exon 8 of 27	NP_001374481.1	A0A804HKL8
	ADGRL3	NM_001322402.3		c.675G>A	p.Ala225Ala	synonymous	Exon 8 of 26	NP_001309331.1
	ADGRL3	NM_001371344.2		c.675G>A	p.Ala225Ala	synonymous	Exon 7 of 24	NP_001358273.1	E7EVD6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL3	ENST00000683033.1	MANE Select	c.675G>A	p.Ala225Ala	synonymous	Exon 8 of 27	ENSP00000507980.1	A0A804HKL8
	ADGRL3	ENST00000512091.6	TSL:1	c.471G>A	p.Ala157Ala	synonymous	Exon 7 of 26	ENSP00000423388.1	Q9HAR2-2
	ADGRL3	ENST00000506720.5	TSL:5	c.675G>A	p.Ala225Ala	synonymous	Exon 6 of 25	ENSP00000420931.1	E7EUW2

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152106 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00432 AC: 1059 AN: 244940 AF XY: 0.00476

Gnomad AFR exome AF: 0.000593

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00875

GnomAD4 exome AF: 0.00366 AC: 5336 AN: 1459596 Hom.: 28 Cov.: 30 AF XY: 0.00387 AC XY: 2807 AN XY: 725900

African (AFR) AF: 0.000927 AC: 31 AN: 33440

American (AMR) AF: 0.00370 AC: 164 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 598 AN: 26072

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39636

South Asian (SAS) AF: 0.00848 AC: 728 AN: 85860

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53262

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5766

European-Non Finnish (NFE) AF: 0.00305 AC: 3392 AN: 1110934

Other (OTH) AF: 0.00478 AC: 288 AN: 60300

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152224 Hom.: 3 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74426

African (AFR) AF: 0.000481 AC: 20 AN: 41542

American (AMR) AF: 0.00307 AC: 47 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 68002

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00396 Hom.: 1

Bravo AF: 0.00289

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.3
DANN	Benign	0.64
PhyloP100		-0.22
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs191915391; hg19: chr4-62598548;