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. The variant received 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. 14/24 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

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40990117).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033030.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BOLL	NM_033030.6	MANE Select	c.554C>T	p.Ala185Val	missense splice_region	Exon 8 of 11	NP_149019.1	Q8N9W6-1
BOLL	NM_001284361.2		c.638C>T	p.Ala213Val	missense splice_region	Exon 9 of 12	NP_001271290.1	Q8N9W6-2
BOLL	NM_197970.3		c.590C>T	p.Ala197Val	missense splice_region	Exon 8 of 11	NP_932074.1	Q8N9W6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BOLL	ENST00000392296.9	TSL:1 MANE Select	c.554C>T	p.Ala185Val	missense splice_region	Exon 8 of 11	ENSP00000376116.4	Q8N9W6-1
BOLL	ENST00000433157.1	TSL:1	c.554C>T	p.Ala185Val	missense splice_region	Exon 8 of 11	ENSP00000396099.1	Q8N9W6-1
ENSG00000222017	ENST00000409845.1	TSL:1	n.167-14458G>A		intron	N/A

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

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

Eigen

Benign

-0.038

Eigen_PC

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.49

M_CAP

Benign

0.013

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

PhyloP100

4.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Uncertain

0.0010

Sift4G

Benign

0.078

Polyphen

0.36

Vest4

0.55

MutPred

0.33

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

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over