NM_213604.3:c.997G>T

Variant names:

• chr19-1506784-C-A
• rs753752128
• NM_213604.3:c.997G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213604.3(ADAMTSL5):​c.997G>T​(p.Ala333Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,390,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. A333T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ADAMTSL5 NM_213604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062129676).

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.997G>T	p.Ala333Ser	missense	Exon 10 of 12	NP_998769.2	X6R4H8
	ADAMTSL5	NM_001367197.1		c.1027G>T	p.Ala343Ser	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.997G>T	p.Ala333Ser	missense	Exon 10 of 12	ENSP00000327608.3	X6R4H8
	ADAMTSL5	ENST00000585700.5	TSL:1	n.1075G>T		non_coding_transcript_exon	Exon 10 of 11
	ADAMTSL5	ENST00000590440.5	TSL:1	n.1035G>T		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390484 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 686240

African (AFR) AF: 0.00 AC: 0 AN: 31274

American (AMR) AF: 0.00 AC: 0 AN: 31640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24360

East Asian (EAS) AF: 0.00 AC: 0 AN: 36322

South Asian (SAS) AF: 0.00 AC: 0 AN: 78576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5150

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1077110

Other (OTH) AF: 0.00 AC: 0 AN: 57456

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.98
DANN	Benign	0.83
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.027
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.017
Sift	Benign	0.48	T
Sift4G	Benign	0.14	T
Vest4		0.18
MVP		0.17
MPC		0.097
ClinPred		0.024	T
GERP RS		1.2
gMVP		0.21
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs753752128; hg19: chr19-1506783;