X-107216683-T-C

Position:

chrX-107216683-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173494.2(DNAAF6):c.166T>C(p.Ser56Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000449 in 111,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DNAAF6
NM_173494.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.541

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]

DNAAF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15212911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF6	NM_173494.2 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	3/7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	4/8		NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAAF6	ENST00000372453.8 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	3/7	1	NM_173494.2	ENSP00000361531.3	Q9NQM4
DNAAF6	ENST00000336387.4 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	3/7	5		ENSP00000337757.4	Q9NQM4
DNAAF6	ENST00000535523.6 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	4/8	5		ENSP00000441930.1	Q9NQM4
DNAAF6	ENST00000688816.1 linkuse as main transcript	c.166T>C	p.Ser56Pro	missense_variant	3/6			ENSP00000508655.1	A0A8I5QJ82

Frequencies

GnomAD3 genomes

AF:

0.0000449

AC:

AN:

111340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33530

show subpopulations

Gnomad AFR

AF:

0.000163

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:

0.00000582

AC:

AN:

171906

Hom.:

AF XY:

0.00

AC XY:

AN XY:

57420

show subpopulations

Gnomad AFR exome

AF:

0.0000792

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1084374

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352330

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000449

AC:

AN:

111340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33530

show subpopulations

Gnomad4 AFR

AF:

0.000163

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:

0.0000302

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2021

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. Algorithms 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PIH1D3-related conditions. This variant is present in population databases (rs376074387, ExAC 0.01%). This sequence change replaces serine with proline at codon 56 of the PIH1D3 protein (p.Ser56Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

T;T;T

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.41

T;.;.

M_CAP

Benign

0.0074

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.25

MVP

0.37

MPC

0.095

ClinPred

0.098

GERP RS

2.9

Varity_R

0.16

gMVP

0.44

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over