2-96124104-A-T

Variant names:

• chr2-96124104-A-T
• rs766863005
• NM_001002036.4:c.1042T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002036.4(ASTL):​c.1042T>A​(p.Ser348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. S348P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASTL NM_001002036.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 0 publications found

Genes affected

ASTL (HGNC:31704): (astacin like metalloendopeptidase) Predicted to enable aspartic-type peptidase activity; glutamic-type peptidase activity; and metalloendopeptidase activity. Predicted to be involved in several processes, including negative regulation of binding activity of sperm to zona pellucida; positive regulation of protein processing; and prevention of polyspermy. Predicted to be located in cortical granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04616213).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002036.4. 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
	ASTL	NM_001002036.4	MANE Select	c.1042T>A	p.Ser348Thr	missense	Exon 9 of 9	NP_001002036.3	Q6HA08

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTL	ENST00000342380.3	TSL:1 MANE Select	c.1042T>A	p.Ser348Thr	missense	Exon 9 of 9	ENSP00000343674.2	Q6HA08
	ASTL	ENST00000867255.1		c.988T>A	p.Ser330Thr	missense	Exon 9 of 9	ENSP00000537314.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244350 AF XY: 0.00000756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452280 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000301 AC: 1 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25570

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105982

Other (OTH) AF: 0.00 AC: 0 AN: 59918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.82
DEOGEN2	Benign	0.00061	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.016
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.024
Sift	Benign	0.35	T
Sift4G	Benign	0.86	T
Polyphen		0.12	B
Vest4		0.16
MVP		0.29
MPC		0.15
ClinPred		0.030	T
GERP RS		-0.12
Varity_R		0.053
gMVP		0.18
Mutation Taster		=100/0	polymorphism

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: rs766863005; hg19: chr2-96789843;