7-105614077-G-A

Position:

• chr7-105614077-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020725.2(ATXN7L1):​c.2257C>T​(p.His753Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,412 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: 0.0000014 (0 hom.)
• Consequence: ATXN7L1 NM_020725.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.92

Genes affected

ATXN7L1 (HGNC:22210): (ataxin 7 like 1)

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=0.30560943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7L1	NM_020725.2	c.2257C>T	p.His753Tyr	missense_variant	10/12	ENST00000419735.8	NP_065776.1
ATXN7L1	NM_001385596.1	c.2257C>T	p.His753Tyr	missense_variant	10/12		NP_001372525.1
ATXN7L1	NM_138495.2	c.1885C>T	p.His629Tyr	missense_variant	8/10		NP_612504.1
ATXN7L1	NM_001318229.2	c.1609C>T	p.His537Tyr	missense_variant	10/10		NP_001305158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7L1	ENST00000419735.8	c.2257C>T	p.His753Tyr	missense_variant	10/12	1	NM_020725.2	ENSP00000410759	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399412 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690202

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: 0.00000185

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.2257C>T (p.H753Y) alteration is located in exon 10 (coding exon 10) of the ATXN7L1 gene. This alteration results from a C to T substitution at nucleotide position 2257, causing the histidine (H) at amino acid position 753 to be replaced by a tyrosine (Y). 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	Benign	0.10
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	0.70	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.96	D;D;.;.
Vest4		0.48
MutPred		0.22		Loss of loop (P = 0.0512);.;.;.;
MVP		0.81
MPC		1.3
ClinPred		0.89	D
GERP RS		3.2
Varity_R		0.23
gMVP		0.41

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: rs769368632; hg19: chr7-105254524;