19-1506822-C-T

Variant names:

• chr19-1506822-C-T
• rs200191805
• NM_213604.3:c.959G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213604.3(ADAMTSL5):​c.959G>A​(p.Arg320Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. R320M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ADAMTSL5 NM_213604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29815367).

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.959G>A	p.Arg320Lys	missense	Exon 10 of 12	NP_998769.2	X6R4H8
	ADAMTSL5	NM_001367197.1		c.989G>A	p.Arg330Lys	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.959G>A	p.Arg320Lys	missense	Exon 10 of 12	ENSP00000327608.3	X6R4H8
	ADAMTSL5	ENST00000585700.5	TSL:1	n.1037G>A		non_coding_transcript_exon	Exon 10 of 11
	ADAMTSL5	ENST00000590440.5	TSL:1	n.997G>A		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388994 Hom.: 0 Cov.: 36 AF XY: 0.00000146 AC XY: 1 AN XY: 685318

African (AFR) AF: 0.00 AC: 0 AN: 31006

American (AMR) AF: 0.00 AC: 0 AN: 31996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24540

East Asian (EAS) AF: 0.00 AC: 0 AN: 35764

South Asian (SAS) AF: 0.00 AC: 0 AN: 78384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076150

Other (OTH) AF: 0.00 AC: 0 AN: 57514

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.84	T
PhyloP100		1.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.095
Sift	Uncertain	0.014	D
Sift4G	Benign	0.068	T
Vest4		0.25
MVP		0.75
MPC		0.12
ClinPred		0.46	T
GERP RS		3.0
gMVP		0.58
Mutation Taster		=79/21	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: rs200191805; hg19: chr19-1506821;