chr20-3471115-C-T

Variant names:

• chr20-3471115-C-T
• rs1487596786
• NM_139321.3:c.8C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139321.3(ATRN):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ATRN NM_139321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.362

Genes affected

ATRN (HGNC:885): (attractin) This gene encodes both membrane-bound and secreted protein isoforms. A membrane-bound isoform exhibits sequence similarity with the mouse mahogany protein, a receptor involved in controlling obesity. A secreted isoform is involved in the initial immune cell clustering during inflammatory responses that may regulate the chemotactic activity of chemokines. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066030085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRN	NM_139321.3	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 29	ENST00000262919.10	NP_647537.1
ATRN	NM_001323332.2	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 26		NP_001310261.1
ATRN	NM_139322.4	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 25		NP_647538.1
ATRN	NM_001207047.3	c.43C>T	p.Leu15Leu	synonymous_variant	Exon 1 of 25		NP_001193976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRN	ENST00000262919.10	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 29	5	NM_139321.3	ENSP00000262919.5
ATRN	ENST00000446916.2	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 25	1		ENSP00000416587.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000930 AC: 1 AN: 107488 Hom.: 0 AF XY: 0.0000167 AC XY: 1 AN XY: 59754

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358338 Hom.: 0 Cov.: 33 AF XY: 0.00000149 AC XY: 1 AN XY: 670288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.36e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the ATRN protein (p.Ala3Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ATRN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.014
Sift	Benign	0.16	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0010	B;B
Vest4		0.10
MutPred		0.29		Gain of catalytic residue at A3 (P = 0.0291);Gain of catalytic residue at A3 (P = 0.0291);
MVP		0.18
MPC		0.73
ClinPred		0.079	T
GERP RS		2.1
Varity_R		0.035
gMVP		0.20

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: rs1487596786; hg19: chr20-3451762;