7-69599693-C-T

Position:

• chr7-69599693-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015570.4(AUTS2):​c.40C>T​(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.649

Genes affected

AUTS2 (HGNC:14262): (activator of transcription and developmental regulator AUTS2) This gene has been implicated in neurodevelopment and as a candidate gene for numerous neurological disorders, including autism spectrum disorders, intellectual disability, and developmental delay. Mutations in this gene have also been associated with non-neurological disorders, such as acute lymphoblastic leukemia, aging of the skin, early-onset androgenetic alopecia, and certain cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38335857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUTS2	NM_015570.4	c.40C>T	p.Arg14Trp	missense_variant	1/19	ENST00000342771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUTS2	ENST00000342771.10	c.40C>T	p.Arg14Trp	missense_variant	1/19	1	NM_015570.4	P4
AUTS2	ENST00000406775.6	c.40C>T	p.Arg14Trp	missense_variant	1/18	1
AUTS2	ENST00000403018.3	c.40C>T	p.Arg14Trp	missense_variant	1/5	1
AUTS2	ENST00000644939.1	c.40C>T	p.Arg14Trp	missense_variant	1/19			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1173726 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 567530

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 27, 2023	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the AUTS2 protein (p.Arg14Trp). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.90	N;N;N
PrimateAI	Pathogenic	0.98	D
Polyphen		0.99, 0.98	.;D;D;.
Vest4		0.32, 0.33, 0.50
MutPred		0.27		Loss of methylation at K12 (P = 0.0542);Loss of methylation at K12 (P = 0.0542);Loss of methylation at K12 (P = 0.0542);Loss of methylation at K12 (P = 0.0542);
MVP		0.33
MPC		2.6
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.23
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-69064679; COSMIC: COSV61423980; COSMIC: COSV61423980;