Genetic Variant DAZL:p.Thr54Pro (chr3-16598169-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001351.4(DAZL):c.160A>C(p.Thr54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. T54A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DAZL
NM_001351.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25

Publications

18 publications found

Variant links:

Genes affected

DAZL (HGNC:2685): (deleted in azoospermia like) The DAZ (Deleted in AZoospermia) gene family encodes potential RNA binding proteins that are expressed in prenatal and postnatal germ cells of males and females. The protein encoded by this gene is localized to the nucleus and cytoplasm of fetal germ cells and to the cytoplasm of developing oocytes. In the testis, this protein is localized to the nucleus of spermatogonia but relocates to the cytoplasm during meiosis where it persists in spermatids and spermatozoa. Transposition and amplification of this autosomal gene during primate evolution gave rise to the DAZ gene cluster on the Y chromosome. Mutations in this gene have been linked to severe spermatogenic failure and infertility in males. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

DAZL Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

DAZL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26054603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAZL	NM_001351.4 link	c.160A>C	p.Thr54Pro	missense_variant	Exon 3 of 11	ENST00000399444.7	NP_001342.2	Q92904-1A0A140VK77
DAZL	NM_001190811.2 link	c.220A>C	p.Thr74Pro	missense_variant	Exon 3 of 11		NP_001177740.1	Q92904-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DAZL	ENST00000399444.7 link	c.160A>C	p.Thr54Pro	missense_variant	Exon 3 of 11	1	NM_001351.4	ENSP00000382373.3	Q92904-1
DAZL	ENST00000250863.12 link	c.220A>C	p.Thr74Pro	missense_variant	Exon 3 of 11	1		ENSP00000250863.8	Q92904-2
DAZL	ENST00000454457.1 link	c.274A>C	p.Thr92Pro	missense_variant	Exon 4 of 7	3		ENSP00000398109.1	E7EV40

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250060

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443076

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33078

American (AMR)

AF:

0.00

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.00

AC:

AN:

39264

South Asian (SAS)

AF:

0.00

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.0000384

AC:

AN:

52108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097834

Other (OTH)

AF:

0.00

AC:

AN:

59204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;T;T

Eigen

Benign

0.025

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.

PhyloP100

2.3

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.10

Sift

Benign

0.076

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.71

.;P;.

Vest4

0.36

MutPred

0.46

.;Loss of phosphorylation at T54 (P = 0.1022);.;

MVP

0.44

MPC

0.68

ClinPred

0.51

GERP RS

3.1

Varity_R

0.62

gMVP

0.62

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over