X-107216704-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_173494.2(DNAAF6):​c.187C>T​(p.Pro63Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000417 in 1,199,956 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000037 ( 0 hom. 0 hem. )

Consequence

DNAAF6
NM_173494.2 missense

Scores

9
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51
Variant links:
Genes affected
DNAAF6 (HGNC:28570): (dynein axonemal assembly factor 6) Enables dynein intermediate chain binding activity. Involved in flagellated sperm motility; inner dynein arm assembly; and outer dynein arm assembly. Located in trans-Golgi network. Implicated in primary ciliary dyskinesia 36. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF6NM_173494.2 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 3/7 ENST00000372453.8 NP_775765.1
DNAAF6NM_001169154.2 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 4/8 NP_001162625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF6ENST00000372453.8 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 3/71 NM_173494.2 ENSP00000361531.3 Q9NQM4
DNAAF6ENST00000336387.4 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 3/75 ENSP00000337757.4 Q9NQM4
DNAAF6ENST00000535523.6 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 4/85 ENSP00000441930.1 Q9NQM4
DNAAF6ENST00000688816.1 linkuse as main transcriptc.187C>T p.Pro63Ser missense_variant 3/6 ENSP00000508655.1 A0A8I5QJ82

Frequencies

GnomAD3 genomes
AF:
0.00000901
AC:
1
AN:
110958
Hom.:
0
Cov.:
23
AF XY:
0.0000301
AC XY:
1
AN XY:
33202
show subpopulations
Gnomad AFR
AF:
0.0000327
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.00000570
AC:
1
AN:
175298
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
60360
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000234
GnomAD4 exome
AF:
0.00000367
AC:
4
AN:
1088998
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
355800
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000288
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000120
Gnomad4 OTH exome
AF:
0.0000437
GnomAD4 genome
AF:
0.00000901
AC:
1
AN:
110958
Hom.:
0
Cov.:
23
AF XY:
0.0000301
AC XY:
1
AN XY:
33202
show subpopulations
Gnomad4 AFR
AF:
0.0000327
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2021Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PIH1D3-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 63 of the PIH1D3 protein (p.Pro63Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;T;T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
T;.;.
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Uncertain
0.019
D
MutationAssessor
Pathogenic
3.0
M;M;M
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-5.9
D;D;D
REVEL
Uncertain
0.39
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.57
MutPred
0.57
Gain of glycosylation at P63 (P = 0.0165);Gain of glycosylation at P63 (P = 0.0165);Gain of glycosylation at P63 (P = 0.0165);
MVP
0.76
MPC
0.38
ClinPred
0.96
D
GERP RS
5.8
Varity_R
0.87
gMVP
0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1408510391; hg19: chrX-106459934; API