7-69599717-C-T

Position:

• chr7-69599717-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000342771.10(AUTS2):​c.64C>T​(p.Arg22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,173,092 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: 0.000011 (0 hom.)
• Consequence: AUTS2 ENST00000342771.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39417452).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.64C>T	p.Arg22Trp	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.64C>T	p.Arg22Trp	missense_variant	1/19	1	NM_015570.4	ENSP00000344087	P4
AUTS2	ENST00000406775.6	c.64C>T	p.Arg22Trp	missense_variant	1/18	1		ENSP00000385263
AUTS2	ENST00000403018.3	c.64C>T	p.Arg22Trp	missense_variant	1/5	1		ENSP00000385572
AUTS2	ENST00000644939.1	c.64C>T	p.Arg22Trp	missense_variant	1/19			ENSP00000496726	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 13 AN: 1173092 Hom.: 0 Cov.: 32 AF XY: 0.00000881 AC XY: 5 AN XY: 567314

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: 0.0000123

Gnomad4 OTH exome AF: 0.0000210

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

GeneDx

Apr 20, 2022

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; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	.;L;L;L
MutationTaster	Benign	0.65	D;D;D
PrimateAI	Pathogenic	0.98	D
PROVEAN	Benign	-1.6	.;N;N;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.28, 0.28, 0.47
MutPred		0.29		Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);Loss of methylation at R27 (P = 0.0258);
MVP		0.29
MPC		2.6
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.19
gMVP		0.22

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: rs1263138285; hg19: chr7-69064703;