17-44195447-G-T

Variant names:

• chr17-44195447-G-T
• rs755871994
• NM_001382309.1:c.593C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001382309.1(ATXN7L3):​c.593C>A​(p.Pro198Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P198L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATXN7L3 NM_001382309.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.37
• Publications: 1 publications found

Genes affected

ATXN7L3 (HGNC:25416): (ataxin 7 like 3) Enables nuclear receptor coactivator activity. Involved in histone deubiquitination; histone monoubiquitination; and positive regulation of transcription, DNA-templated. Located in nucleus. Part of DUBm complex and SAGA complex. [provided by Alliance of Genome Resources, Apr 2022]

ATXN7L3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37671596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382309.1. 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
	ATXN7L3	NM_001382309.1	MANE Select	c.593C>A	p.Pro198Gln	missense	Exon 9 of 13	NP_001369238.1	Q14CW9-1
	ATXN7L3	NM_001382316.1		c.650C>A	p.Pro217Gln	missense	Exon 9 of 13	NP_001369245.1
	ATXN7L3	NM_001382308.1		c.614C>A	p.Pro205Gln	missense	Exon 9 of 13	NP_001369237.1	Q14CW9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7L3	ENST00000587097.6	TSL:5 MANE Select	c.593C>A	p.Pro198Gln	missense	Exon 9 of 13	ENSP00000465614.2	Q14CW9-1
	ATXN7L3	ENST00000454077.6	TSL:1	c.614C>A	p.Pro205Gln	missense	Exon 8 of 12	ENSP00000397259.1	Q14CW9-2
	ATXN7L3	ENST00000389384.8	TSL:1	c.593C>A	p.Pro198Gln	missense	Exon 8 of 12	ENSP00000374035.3	Q14CW9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249482 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

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: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.21
Sift	Benign	0.036	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.79
MutPred		0.36		Loss of glycosylation at P198 (P = 0.0662)
MVP		0.43
MPC		1.1
ClinPred		0.72	D
GERP RS		3.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.12
gMVP		0.90

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: rs755871994; hg19: chr17-42272815;