7-69599669-C-T

Position:

• chr7-69599669-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.16C>T​(p.Arg6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000866 in 1,154,534 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: 8.7e-7 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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=0.39441597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AUTS2	NM_015570.4	c.16C>T	p.Arg6Trp	missense_variant	1/19	ENST00000342771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AUTS2	ENST00000342771.10	c.16C>T	p.Arg6Trp	missense_variant	1/19	1	NM_015570.4	P4
AUTS2	ENST00000406775.6	c.16C>T	p.Arg6Trp	missense_variant	1/18	1
AUTS2	ENST00000403018.3	c.16C>T	p.Arg6Trp	missense_variant	1/5	1
AUTS2	ENST00000644939.1	c.16C>T	p.Arg6Trp	missense_variant	1/19			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.66e-7 AC: 1 AN: 1154534 Hom.: 0 Cov.: 32 AF XY: 0.00000180 AC XY: 1 AN XY: 555894

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: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.16C>T (p.R6W) alteration is located in exon 1 (coding exon 1) of the AUTS2 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;.;T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	.;L;L;L
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.57	.;N;N;N
REVEL	Benign	0.077
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		0.89	.;P;P;.
Vest4		0.25, 0.21, 0.28
MutPred		0.33		Loss of methylation at R6 (P = 0.0069);Loss of methylation at R6 (P = 0.0069);Loss of methylation at R6 (P = 0.0069);Loss of methylation at R6 (P = 0.0069);
MVP		0.23
MPC		2.6
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.25
gMVP		0.13

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: rs1368494641; hg19: chr7-69064655;