6-116616611-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001010892.3(RSPH4A):c.-13T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,605,164 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: RSPH4A NM_001010892.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.508

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-116616611-T-A is Benign according to our data. Variant chr6-116616611-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1707228.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (666/152192) while in subpopulation AFR AF= 0.0151 (626/41532). AF 95% confidence interval is 0.0141. There are 4 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.-13T>A		5_prime_UTR_variant	1/6	ENST00000229554.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.-13T>A		5_prime_UTR_variant	1/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.-13T>A		5_prime_UTR_variant	1/5	1
RSPH4A	ENST00000368580.4			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152074 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

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: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000593 AC: 140 AN: 235988 Hom.: 1 AF XY: 0.000532 AC XY: 68 AN XY: 127904

Gnomad AFR exome AF: 0.00814

Gnomad AMR exome AF: 0.000665

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: 0.00000951

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000421 AC: 612 AN: 1452972 Hom.: 5 Cov.: 30 AF XY: 0.000363 AC XY: 262 AN XY: 722044

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.00109

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: 0.0000154

Gnomad4 OTH exome AF: 0.000915

GnomAD4 genome AF: 0.00438 AC: 666 AN: 152192 Hom.: 4 Cov.: 31 AF XY: 0.00418 AC XY: 311 AN XY: 74390

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00219 Hom.: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2015

The c.-13T>A alteration is located in the 5' untranslated region (5'UTR) of the RSPH4A gene. This alteration consists of a T to A substitution nucleotides upstream from the first translated codon. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.0
Dann	Benign	0.73

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: rs567530388; hg19: chr6-116937774;