19-1506807-C-T

Variant names:

• chr19-1506807-C-T
• rs777151542
• NM_213604.3:c.974G>A

Variant summary

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

The NM_213604.3(ADAMTSL5):​c.974G>A​(p.Arg325Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000973 in 1,541,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ADAMTSL5 NM_213604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.573
• Publications: 1 publications found

Genes affected

ADAMTSL5 (HGNC:27912): (ADAMTS like 5) Enables heparin binding activity and microfibril binding activity. Located in extracellular region and microfibril. [provided by Alliance of Genome Resources, Apr 2022]

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=0.24878159).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213604.3. 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
	ADAMTSL5	NM_213604.3	MANE Select	c.974G>A	p.Arg325Gln	missense	Exon 10 of 12	NP_998769.2	X6R4H8
	ADAMTSL5	NM_001367197.1		c.1004G>A	p.Arg335Gln	missense	Exon 11 of 13	NP_001354126.1	Q6ZMM2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL5	ENST00000330475.9	TSL:2 MANE Select	c.974G>A	p.Arg325Gln	missense	Exon 10 of 12	ENSP00000327608.3	X6R4H8
	ADAMTSL5	ENST00000585700.5	TSL:1	n.1052G>A		non_coding_transcript_exon	Exon 10 of 11
	ADAMTSL5	ENST00000590440.5	TSL:1	n.1012G>A		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151936 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000140 AC: 2 AN: 142386 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1389168 Hom.: 0 Cov.: 36 AF XY: 0.0000131 AC XY: 9 AN XY: 685406

African (AFR) AF: 0.00 AC: 0 AN: 31074

American (AMR) AF: 0.00 AC: 0 AN: 31968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24480

East Asian (EAS) AF: 0.00 AC: 0 AN: 35888

South Asian (SAS) AF: 0.0000509 AC: 4 AN: 78522

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 0.00000836 AC: 9 AN: 1076236

Other (OTH) AF: 0.00 AC: 0 AN: 57454

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74198

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.082
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.74	T
PhyloP100		0.57
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.043	D
Sift4G	Uncertain	0.030	D
Vest4		0.26
MVP		0.41
MPC		0.28
ClinPred		0.73	D
GERP RS		3.0
gMVP		0.37
Mutation Taster		=87/13	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: rs777151542; hg19: chr19-1506806;