rs775335375

Variant names:

• chrX-107238994-C-T
• rs775335375
• NM_173494.2:c.502C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_173494.2(DNAAF6):​c.502C>T​(p.Arg168Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,207,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000055 (0 hom. 23 hem.)
• Consequence: DNAAF6 NM_173494.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32592106).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF6	NM_173494.2	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2	c.502C>T	p.Arg168Cys	missense_variant	Exon 7 of 8		NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF6	ENST00000372453.8	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	1	NM_173494.2	ENSP00000361531.3
DNAAF6	ENST00000336387.4	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	5		ENSP00000337757.4
DNAAF6	ENST00000535523.6	c.502C>T	p.Arg168Cys	missense_variant	Exon 7 of 8	5		ENSP00000441930.1
DNAAF6	ENST00000688816.1	c.405C>T	p.Phe135Phe	synonymous_variant	Exon 5 of 6			ENSP00000508655.1

Frequencies

GnomAD3 genomes AF: 0.0000448 AC: 5 AN: 111537 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33731

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000501 AC: 9 AN: 179770 Hom.: 0 AF XY: 0.0000155 AC XY: 1 AN XY: 64666

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: 0.000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 60 AN: 1095972 Hom.: 0 Cov.: 30 AF XY: 0.0000636 AC XY: 23 AN XY: 361672

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000448 AC: 5 AN: 111537 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33731

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000168

Gnomad4 NFE AF: 0.0000565

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000110

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ciliary dyskinesia, primary, 36, X-linked Uncertain:1

Jul 10, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the PIH1D3 protein (p.Arg168Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PIH1D3-related conditions. ClinVar contains an entry for this variant (Variation ID: 562215). 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 disruptive. 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Benign	0.14
Sift	Benign	0.039	D;D;D
Sift4G	Benign	0.082	T;T;T
Polyphen		0.94	P;P;P
Vest4		0.51
MVP		0.28
MPC		0.28
ClinPred		0.73	D
GERP RS		3.7
Varity_R		0.35
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs775335375; hg19: chrX-106482224;