7-70764832-C-T

Variant names:

• chr7-70764832-C-T
• rs767529359
• NM_015570.4:c.1295C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015570.4(AUTS2):​c.1295C>T​(p.Pro432Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000834 in 1,199,624 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P432H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 1 publications found

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]

AUTS2 Gene-Disease associations (from GenCC):

• autism spectrum disorder due to AUTS2 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015570.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	NM_015570.4	MANE Select	c.1295C>T	p.Pro432Leu	missense	Exon 8 of 19	NP_056385.1	Q8WXX7-1
	AUTS2	NM_001127231.3		c.1295C>T	p.Pro432Leu	missense	Exon 8 of 18	NP_001120703.1	Q8WXX7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUTS2	ENST00000342771.10	TSL:1 MANE Select	c.1295C>T	p.Pro432Leu	missense	Exon 8 of 19	ENSP00000344087.4	Q8WXX7-1
	AUTS2	ENST00000406775.6	TSL:1	c.1295C>T	p.Pro432Leu	missense	Exon 8 of 18	ENSP00000385263.2	Q8WXX7-2
	AUTS2	ENST00000644939.1		c.1292C>T	p.Pro431Leu	missense	Exon 8 of 19	ENSP00000496726.1	A0A2R8Y8C6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 170110 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.34e-7 AC: 1 AN: 1199624 Hom.: 0 Cov.: 19 AF XY: 0.00000166 AC XY: 1 AN XY: 601326

African (AFR) AF: 0.00 AC: 0 AN: 28124

American (AMR) AF: 0.00 AC: 0 AN: 36772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23814

East Asian (EAS) AF: 0.00 AC: 0 AN: 35308

South Asian (SAS) AF: 0.00 AC: 0 AN: 76108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 892646

Other (OTH) AF: 0.00 AC: 0 AN: 51568

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000844 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.24
MPC		0.44
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.53
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs767529359; hg19: chr7-70229818;