7-69599732-C-T

Position:

• chr7-69599732-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.79C>T​(p.Arg27Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000852 in 1,173,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 8.5e-7 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.217

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=0.30025923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.79C>T	p.Arg27Trp	missense_variant	1/19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.79C>T	p.Arg27Trp	missense_variant	1/19	1	NM_015570.4	ENSP00000344087	P4
AUTS2	ENST00000406775.6	c.79C>T	p.Arg27Trp	missense_variant	1/18	1		ENSP00000385263
AUTS2	ENST00000403018.3	c.79C>T	p.Arg27Trp	missense_variant	1/5	1		ENSP00000385572
AUTS2	ENST00000644939.1	c.79C>T	p.Arg27Trp	missense_variant	1/19			ENSP00000496726	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.52e-7 AC: 1 AN: 1173664 Hom.: 0 Cov.: 32 AF XY: 0.00000176 AC XY: 1 AN XY: 567704

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: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the AUTS2 protein (p.Arg27Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AUTS2-related conditions. 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. 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	.;.;T;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.85	T;D;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	.;N;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.2	.;N;N;D
REVEL	Benign	0.058
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0030	.;D;D;D
Polyphen		0.95	.;P;P;.
Vest4		0.20, 0.27, 0.20
MutPred		0.26		Loss of methylation at R27 (P = 0.0099);Loss of methylation at R27 (P = 0.0099);Loss of methylation at R27 (P = 0.0099);Loss of methylation at R27 (P = 0.0099);
MVP		0.14
MPC		2.6
ClinPred		0.68	D
GERP RS		1.6
Varity_R		0.15
gMVP		0.12

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: chr7-69064718;