Genetic Variant NM_033030.6:c.554C>T (chr2-197757399-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_033030.6(BOLL):c.554C>T(p.Ala185Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000658 in 151,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A185D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

BOLL
NM_033030.6 missense, splice_region

Scores

Splicing: ADA: 0.005253

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

BOLL (HGNC:14273): (boule homolog, RNA binding protein) This gene belongs to the DAZ gene family required for germ cell development. It encodes an RNA-binding protein which is more similar to Drosophila Boule than to human proteins encoded by genes DAZ (deleted in azoospermia) or DAZL (deleted in azoospermia-like). Loss of this gene function results in the absence of sperm in semen (azoospermia). Histological studies demonstrated that the primary defect is at the meiotic G2/M transition. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

BOLL links:

ENSG00000222017 (HGNC:):

ENSG00000222017 links:

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ACMG classification

Classification made for transcript

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=0.40990117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BOLL	NM_033030.6 link	c.554C>T	p.Ala185Val	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000392296.9	NP_149019.1	Q8N9W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BOLL	ENST00000392296.9 link	c.554C>T	p.Ala185Val	missense_variant, splice_region_variant	Exon 8 of 11	1	NM_033030.6	ENSP00000376116.4		Q8N9W6-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;T;.;.;T

Eigen

Benign

-0.038

Eigen_PC

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.49

T;.;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

.;L;.;.;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

N;N;D;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;T;D;T;T

Sift4G

Benign

0.078

T;T;D;T;T

Polyphen

0.36, 0.0040

.;B;.;B;B

Vest4

0.55

MutPred

0.33

.;Gain of catalytic residue at A185 (P = 0.0856);.;.;Gain of catalytic residue at A185 (P = 0.0856);

MVP

0.33

MPC

0.39

ClinPred

0.81

GERP RS

4.9

Varity_R

0.086

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0053

dbscSNV1_RF

Benign

0.030

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over