19-1421245-A-T

Variant names:

• chr19-1421245-A-T
• NM_018959.4:c.401A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001352035.2(DAZAP1):​c.-36A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DAZAP1 NM_001352035.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

DAZAP1 (HGNC:2683): (DAZ associated protein 1) In mammals, the Y chromosome directs the development of the testes and plays an important role in spermatogenesis. A high percentage of infertile men have deletions that map to regions of the Y chromosome. The DAZ (deleted in azoospermia) gene cluster maps to the AZFc region of the Y chromosome and is deleted in many azoospermic and severely oligospermic men. It is thought that the DAZ gene cluster arose from the transposition, amplification, and pruning of the ancestral autosomal gene DAZL also involved in germ cell development and gametogenesis. This gene encodes a RNA-binding protein with two RNP motifs that was originally identified by its interaction with the infertility factors DAZ and DAZL. Two isoforms are encoded by transcript variants of this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAZAP1	NM_018959.4	c.401A>T	p.Lys134Met	missense_variant	Exon 5 of 12	ENST00000233078.9	NP_061832.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAZAP1	ENST00000233078.9	c.401A>T	p.Lys134Met	missense_variant	Exon 5 of 12	1	NM_018959.4	ENSP00000233078.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.401A>T (p.K134M) alteration is located in exon 5 (coding exon 5) of the DAZAP1 gene. This alteration results from a A to T substitution at nucleotide position 401, causing the lysine (K) at amino acid position 134 to be replaced by a methionine (M). 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;.;T;T
Eigen	Benign	0.021
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.4	L;L;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;N;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.11	T;T;.;.;.
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.13	B;B;.;.;.
Vest4		0.49
MutPred		0.54		Loss of methylation at K134 (P = 0.0109);Loss of methylation at K134 (P = 0.0109);Loss of methylation at K134 (P = 0.0109);.;.;
MVP		0.81
MPC		1.6
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1421244;