rs201505307

Positions:

• chr15-88856926-G-C
• chr15-88856926-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001369268.1(ACAN):​c.4341G>C​(p.Glu1447Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 131,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.07

Genes affected

ACAN (HGNC:319): (aggrecan) This gene is a member of the aggrecan/versican proteoglycan family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage. Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration. Multiple alternatively spliced transcript variants that encode different protein isoforms have been observed in this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005847603).
• BP6: Variant 15-88856926-G-C is Benign according to our data. Variant chr15-88856926-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 402334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000534 (70/131048) while in subpopulation AFR AF= 0.00104 (36/34484). AF 95% confidence interval is 0.000774. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAN	NM_001369268.1	c.4341G>C	p.Glu1447Asp	missense_variant	12/19	ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.4341G>C	p.Glu1447Asp	missense_variant	12/19	3	NM_001369268.1	P1

Frequencies

GnomAD3 genomes AF: 0.000535 AC: 70 AN: 130954 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000438

Gnomad ASJ AF: 0.000319

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.000547

Gnomad MID AF: 0.00543

Gnomad NFE AF: 0.000217

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248098 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134646

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000188 AC: 27 AN: 1437086 Hom.: 0 Cov.: 42 AF XY: 0.0000224 AC XY: 16 AN XY: 715296

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000519

Gnomad4 SAS exome AF: 0.0000587

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome AF: 0.000534 AC: 70 AN: 131048 Hom.: 0 Cov.: 31 AF XY: 0.000511 AC XY: 33 AN XY: 64624

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000438

Gnomad4 ASJ AF: 0.000319

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.00102

Gnomad4 FIN AF: 0.000547

Gnomad4 NFE AF: 0.000217

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000959 Hom.: 0

ExAC AF: 0.000555 AC: 67

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.6% of African chromosomes in ExAC, frequency high for disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.0010
DANN	Benign	0.25
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.29	T;T;T;T;T;.
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.0058	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
Vest4		0.029, 0.032, 0.036, 0.037, 0.022
MutPred		0.27		Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);.;Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);
MVP		0.14
MPC		0.18
ClinPred		0.023	T
GERP RS		-5.3
Varity_R		0.032
gMVP		0.055

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

LitVar

Other links and lift over

dbSNP: rs201505307; hg19: chr15-89400157; COSMIC: COSV61359601;