Genetic Variant ADAMTSL5:p.Arg311His (chr19-1506849-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_213604.3(ADAMTSL5):c.932G>A(p.Arg311His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,391,400 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. R311P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ADAMTSL5
NM_213604.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

2 publications found

Variant links:

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]

ADAMTSL5 links:

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ACMG classification

Classification was made for transcript

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=0.06326872).

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.932G>A	p.Arg311His	missense	Exon 10 of 12	NP_998769.2	X6R4H8
	ADAMTSL5	NM_001367197.1		c.962G>A	p.Arg321His	missense	Exon 11 of 13	NP_001354126.1	Q6ZMM2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTSL5	ENST00000330475.9	TSL:2 MANE Select	c.932G>A	p.Arg311His	missense	Exon 10 of 12	ENSP00000327608.3	X6R4H8
ADAMTSL5	ENST00000585700.5	TSL:1	n.1010G>A		non_coding_transcript_exon	Exon 10 of 11
ADAMTSL5	ENST00000590440.5	TSL:1	n.970G>A		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000691

AC:

AN:

144820

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1391400

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

686490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31136

American (AMR)

AF:

0.00

AC:

AN:

32942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24732

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

78500

European-Finnish (FIN)

AF:

0.0000207

AC:

AN:

48350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.0000158

AC:

AN:

1076884

Other (OTH)

AF:

0.00

AC:

AN:

57638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.014

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.0052

LIST_S2

Benign

0.83

M_CAP

Benign

0.026

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.97

PhyloP100

1.1

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.87

REVEL

Benign

0.051

Sift

Benign

0.15

Sift4G

Benign

0.18

Vest4

0.22

MVP

0.22

MPC

0.13

ClinPred

0.040

GERP RS

1.6

gMVP

0.33

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over