13-95589189-C-A

Variant names:

• chr13-95589189-C-A
• NM_198968.4:c.1992G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198968.4(DZIP1):​c.1992G>T​(p.Met664Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M664L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DZIP1 NM_198968.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0570
• Publications: 0 publications found

Genes affected

DZIP1 (HGNC:20908): (DAZ interacting zinc finger protein 1) Predicted to enable metal ion binding activity. Involved in cilium assembly; germ cell development; and spermatogenesis. Located in cytosol; microtubule organizing center; and nucleoplasm. Colocalizes with centriole. Implicated in mitral valve prolapse and spermatogenic failure 47. [provided by Alliance of Genome Resources, Apr 2022]

DZIP1 Gene-Disease associations (from GenCC):

• spermatogenic failure 47

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041134626).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198968.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DZIP1	NM_198968.4	MANE Select	c.1992G>T	p.Met664Ile	missense	Exon 19 of 23	NP_945319.1	Q86YF9-1
	DZIP1	NM_014934.5		c.1935G>T	p.Met645Ile	missense	Exon 18 of 22	NP_055749.1	Q86YF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DZIP1	ENST00000376829.7	TSL:1 MANE Select	c.1992G>T	p.Met664Ile	missense	Exon 19 of 23	ENSP00000366025.2	Q86YF9-1
	DZIP1	ENST00000361396.6	TSL:1	c.1935G>T	p.Met645Ile	missense	Exon 18 of 22	ENSP00000355175.2	Q86YF9-2
	DZIP1	ENST00000926439.1		c.2046G>T	p.Met682Ile	missense	Exon 16 of 20	ENSP00000596498.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.6
DANN	Benign	0.60
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.057
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.019
Sift	Benign	0.35	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.25		Loss of helix (P = 0.0033)
MVP		0.24
MPC		0.083
ClinPred		0.051	T
GERP RS		-4.2
Varity_R		0.038
gMVP		0.071
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr13-96241443;