chr11-125678121-T-G

Position:

• chr11-125678121-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001612.6(ACRV1):​c.229A>C​(p.Lys77Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACRV1 NM_001612.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

ACRV1 (HGNC:127): (acrosomal vesicle protein 1) This gene encodes a testis-specific, differentiation antigen, acrosomal vesicle protein 1, that arises within the acrosomal vesicle during spermatogenesis, and is associated with the acrosomal membranes and matrix of mature sperm. The acrosomal vesicle protein 1 may be involved in sperm-zona binding or penetration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2010]

CHEK1 (HGNC:):

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=0.064536184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACRV1	NM_001612.6	c.229A>C	p.Lys77Gln	missense_variant	2/4	ENST00000533904.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACRV1	ENST00000533904.6	c.229A>C	p.Lys77Gln	missense_variant	2/4	1	NM_001612.6	A2
ACRV1	ENST00000315608.7	c.229A>C	p.Lys77Gln	missense_variant	2/4	1		P2
ACRV1	ENST00000527795.1	c.122-103A>C		intron_variant		2		A2
ACRV1	ENST00000530048.5	c.122-58A>C		intron_variant		3		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 31

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

Jan 04, 2022

The c.229A>C (p.K77Q) alteration is located in exon 2 (coding exon 2) of the ACRV1 gene. This alteration results from a A to C substitution at nucleotide position 229, causing the lysine (K) at amino acid position 77 to be replaced by a glutamine (Q). 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	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.0
DANN	Benign	0.79
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.015
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.21		Loss of ubiquitination at K77 (P = 0.0071);Loss of ubiquitination at K77 (P = 0.0071);
MVP		0.18
MPC		0.25
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.092
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: rs1591439276; hg19: chr11-125548016;