X-107212900-G-C

Position:

chrX-107212900-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_173494.2(DNAAF6):c.25G>C(p.Glu9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,194,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000065 ( 0 hom. 1 hem. )

Consequence

DNAAF6
NM_173494.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14077848).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000647 (7/1082427) while in subpopulation AFR AF= 0.000234 (6/25598). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF6	NM_173494.2 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	2/7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	3/8		NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAAF6	ENST00000372453.8 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	2/7	1	NM_173494.2	ENSP00000361531.3	Q9NQM4
DNAAF6	ENST00000336387.4 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	2/7	5		ENSP00000337757.4	Q9NQM4
DNAAF6	ENST00000535523.6 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	3/8	5		ENSP00000441930.1	Q9NQM4
DNAAF6	ENST00000688816.1 linkuse as main transcript	c.25G>C	p.Glu9Gln	missense_variant	2/6			ENSP00000508655.1	A0A8I5QJ82

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

111985

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34159

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

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:

0.0000183

AC:

AN:

163981

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52563

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.0000432

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

AF:

0.00000647

AC:

AN:

1082427

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

352019

show subpopulations

Gnomad4 AFR exome

AF:

0.000234

Gnomad4 AMR exome

AF:

0.0000312

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:

0.0000536

AC:

AN:

111985

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34159

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.0000948

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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

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

Nov 10, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 9 of the PIH1D3 protein (p.Glu9Gln). This variant is present in population databases (rs770708166, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PIH1D3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.010

T;T;T

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.43

T;.;.

M_CAP

Benign

0.0028

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

L;L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.45

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.11

T;T;T

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.12

MutPred

0.041

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.10

MPC

0.072

ClinPred

0.079

GERP RS

3.7

Varity_R

0.085

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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