X-107212906-A-C

Position:

• chrX-107212906-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173494.2(DNAAF6):​c.31A>C​(p.Met11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,085,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: DNAAF6 NM_173494.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04633501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF6	NM_173494.2	c.31A>C	p.Met11Leu	missense_variant	2/7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2	c.31A>C	p.Met11Leu	missense_variant	3/8		NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF6	ENST00000372453.8	c.31A>C	p.Met11Leu	missense_variant	2/7	1	NM_173494.2	ENSP00000361531.3
DNAAF6	ENST00000336387.4	c.31A>C	p.Met11Leu	missense_variant	2/7	5		ENSP00000337757.4
DNAAF6	ENST00000535523.6	c.31A>C	p.Met11Leu	missense_variant	3/8	5		ENSP00000441930.1
DNAAF6	ENST00000688816.1	c.31A>C	p.Met11Leu	missense_variant	2/6			ENSP00000508655.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085540 Hom.: 0 Cov.: 29 AF XY: 0.00000283 AC XY: 1 AN XY: 353696

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000220

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2022

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. This missense change has been observed in individual(s) with clinical features of PIH1D3-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the PIH1D3 protein (p.Met11Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.34
DANN	Benign	0.45
DEOGEN2	Benign	0.0087	T;T;T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.29	T;.;.
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.062
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.18
MutPred		0.061		Gain of methylation at K12 (P = 0.0893);Gain of methylation at K12 (P = 0.0893);Gain of methylation at K12 (P = 0.0893);
MVP		0.043
MPC		0.062
ClinPred		0.065	T
GERP RS		-6.9
Varity_R		0.092
gMVP		0.35

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

Other links and lift over

dbSNP: rs1385499843; hg19: chrX-106456136;