X-107212928-C-T

Position:

chrX-107212928-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_173494.2(DNAAF6):c.53C>T(p.Ser18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,202,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

DNAAF6
NM_173494.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.136

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048490047).

BS2

High Hemizygotes in GnomAdExome4 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.53C>T	p.Ser18Phe	missense_variant	2/7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2 linkuse as main transcript	c.53C>T	p.Ser18Phe	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.53C>T	p.Ser18Phe	missense_variant	2/7	1	NM_173494.2	ENSP00000361531.3	Q9NQM4
DNAAF6	ENST00000336387.4 linkuse as main transcript	c.53C>T	p.Ser18Phe	missense_variant	2/7	5		ENSP00000337757.4	Q9NQM4
DNAAF6	ENST00000535523.6 linkuse as main transcript	c.53C>T	p.Ser18Phe	missense_variant	3/8	5		ENSP00000441930.1	Q9NQM4
DNAAF6	ENST00000688816.1 linkuse as main transcript	c.53C>T	p.Ser18Phe	missense_variant	2/6			ENSP00000508655.1	A0A8I5QJ82

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34146

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000580

AC:

AN:

172475

Hom.:

AF XY:

0.00

AC XY:

AN XY:

57949

show subpopulations

Gnomad AFR exome

AF:

0.0000790

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

AF:

0.00000367

AC:

AN:

1090586

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

357080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000383

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:

0.00000358

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34146

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

Mar 30, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 1683169). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). 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 0.008%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 18 of the PIH1D3 protein (p.Ser18Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.2

DANN

Benign

0.098

DEOGEN2

Benign

0.013

T;T;T

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.35

T;.;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.10

MutPred

0.16

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.043

MPC

0.064

ClinPred

0.021

GERP RS

1.6

Varity_R

0.088

gMVP

0.33

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