rs141055331

chr3-50342543-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015896.4(ZMYND10):c.727C>T(p.Arg243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000898 in 1,613,592 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: ZMYND10 NM_015896.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.345

Genes affected

ZMYND10 (HGNC:19412): (zinc finger MYND-type containing 10) This gene encodes a protein containing a MYND-type zinc finger domain that likely functions in assembly of the dynein motor. Mutations in this gene can cause primary ciliary dyskinesia. This gene is also considered a tumor suppressor gene and is often mutated, deleted, or hypermethylated and silenced in cancer cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ZMYND10-AS1 (HGNC:40890): (ZMYND10 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011281699).
• BP6: Variant 3-50342543-G-A is Benign according to our data. Variant chr3-50342543-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00316 (481/152296) while in subpopulation AFR AF= 0.00897 (373/41560). AF 95% confidence interval is 0.00822. There are 2 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYND10	NM_015896.4	c.727C>T	p.Arg243Cys	missense_variant	8/12	ENST00000231749.8
ZMYND10	NM_001308379.2	c.712C>T	p.Arg238Cys	missense_variant	7/11
ZMYND10	XM_005265216.4	c.490C>T	p.Arg164Cys	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYND10	ENST00000231749.8	c.727C>T	p.Arg243Cys	missense_variant	8/12	1	NM_015896.4	P1
ZMYND10-AS1	ENST00000440013.1	n.123+1315G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00900

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

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: 0.000603

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 250592 Hom.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135522

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000539

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000662 AC: 968 AN: 1461296 Hom.: 1 Cov.: 32 AF XY: 0.000655 AC XY: 476 AN XY: 726818

Gnomad4 AFR exome AF: 0.00843

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000462

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00301 AC XY: 224 AN XY: 74470

Gnomad4 AFR AF: 0.00897

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.000960 Hom.: 0

Bravo AF: 0.00377

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ZMYND10: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.011	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.26
MVP		0.030
MPC		0.22
ClinPred		0.036	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs141055331; hg19: chr3-50379974;