2-96124104-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTL	NM_001002036.4	c.1042T>A	p.Ser348Thr	missense_variant	Exon 9 of 9	ENST00000342380.3	NP_001002036.3
ASTL	XM_011511205.3	c.1057T>A	p.Ser353Thr	missense_variant	Exon 8 of 8		XP_011509507.1
ASTL	XM_011511207.3	c.1003T>A	p.Ser335Thr	missense_variant	Exon 8 of 8		XP_011509509.1
ASTL	XM_011511208.3	c.*143T>A		3_prime_UTR_variant	Exon 7 of 7		XP_011509510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASTL	ENST00000342380.3	c.1042T>A	p.Ser348Thr	missense_variant	Exon 9 of 9	1	NM_001002036.4	ENSP00000343674.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244350 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132288

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

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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: rs766863005; hg19: chr2-96789843;