rs143679158

Variant names:

• chr7-70764784-A-G
• rs143679158
• NM_015570.4:c.1247A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015570.4(AUTS2):​c.1247A>G​(p.Gln416Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 816,374 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: AUTS2 NM_015570.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.22

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064305186).
• BP6: Variant 7-70764784-A-G is Benign according to our data. Variant chr7-70764784-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547994.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000112 (17/151266) while in subpopulation SAS AF= 0.000209 (1/4784). AF 95% confidence interval is 0.0000907. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AUTS2	NM_015570.4	c.1247A>G	p.Gln416Arg	missense_variant	Exon 8 of 19	ENST00000342771.10	NP_056385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AUTS2	ENST00000342771.10	c.1247A>G	p.Gln416Arg	missense_variant	Exon 8 of 19	1	NM_015570.4	ENSP00000344087.4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151148 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000130 AC: 20 AN: 153802 Hom.: 0 AF XY: 0.000135 AC XY: 11 AN XY: 81276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000177 AC: 118 AN: 665108 Hom.: 0 Cov.: 9 AF XY: 0.000210 AC XY: 74 AN XY: 352780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000493

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151266 Hom.: 0 Cov.: 30 AF XY: 0.0000541 AC XY: 4 AN XY: 73912

Gnomad4 AFR AF: 0.0000730

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000228 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000370 AC: 3

ExAC AF: 0.0000909 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism spectrum disorder due to AUTS2 deficiency Uncertain:1

Sep 08, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.019	.;.;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.79	.;N;N;.;.
REVEL	Benign	0.030
Sift	Benign	0.79	.;T;T;.;.
Sift4G	Benign	0.52	.;T;T;T;T
Polyphen		0.95	.;P;P;.;.
Vest4		0.45, 0.35
MVP		0.33
MPC		0.78
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143679158; hg19: chr7-70229770;