Variant chrX-107216715-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173494.2(DNAAF6):c.198T>G(p.Ile66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 111,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Consequence

DNAAF6
NM_173494.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF6	NM_173494.2 linkuse as main transcript	c.198T>G	p.Ile66Met	missense_variant	3/7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2 linkuse as main transcript	c.198T>G	p.Ile66Met	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.198T>G	p.Ile66Met	missense_variant	3/7	1	NM_173494.2	ENSP00000361531.3	Q9NQM4
DNAAF6	ENST00000336387.4 linkuse as main transcript	c.198T>G	p.Ile66Met	missense_variant	3/7	5		ENSP00000337757.4	Q9NQM4
DNAAF6	ENST00000535523.6 linkuse as main transcript	c.198T>G	p.Ile66Met	missense_variant	4/8	5		ENSP00000441930.1	Q9NQM4
DNAAF6	ENST00000688816.1 linkuse as main transcript	c.198T>G	p.Ile66Met	missense_variant	3/6			ENSP00000508655.1	A0A8I5QJ82

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111387

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33591

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000570

AC:

AN:

175383

Hom.:

AF XY:

0.00

AC XY:

AN XY:

60403

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:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111387

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33591

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Oct 23, 2021

This variant has not been reported in the literature in individuals affected with PIH1D3-related conditions. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 is present in population databases (rs760885373, gnomAD 0.001%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 66 of the PIH1D3 protein (p.Ile66Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

T;.;.

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Uncertain

-0.021

MutationAssessor

Pathogenic

3.3

M;M;M

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.51

MutPred

0.54

Loss of catalytic residue at I66 (P = 0.0427);Loss of catalytic residue at I66 (P = 0.0427);Loss of catalytic residue at I66 (P = 0.0427);

MVP

0.48

MPC

0.38

ClinPred

0.91

GERP RS

5.8

Varity_R

0.69

gMVP

0.43

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