6-116630598-C-G

Variant names:

• chr6-116630598-C-G
• rs10485188
• NM_001010892.3:c.1916+46C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010892.3(RSPH4A):​c.1916+46C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 889,158 control chromosomes in the GnomAD database, including 2,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (381 hom., cov: 31)
  • Exomes 𝑓: 0.053 (1888 hom.)
• Consequence: RSPH4A NM_001010892.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0930
• Publications: 4 publications found

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]

RSPH4A Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901386 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-116630598-C-G is Benign according to our data. Variant chr6-116630598-C-G is described in ClinVar as [Benign]. Clinvar id is 257050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1916+46C>G		intron_variant	Intron 5 of 5	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1916+46C>G		intron_variant	Intron 5 of 5	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.1780+46C>G		intron_variant	Intron 4 of 4	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.1175+46C>G		intron_variant	Intron 4 of 4	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9124 AN: 150492 Hom.: 379 Cov.: 31

Gnomad AFR AF: 0.0714

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0673

GnomAD2 exomes AF: 0.0711 AC: 17836 AN: 250998 AF XY: 0.0648

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.0473

Gnomad EAS exome AF: 0.0173

Gnomad FIN exome AF: 0.0301

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0672

GnomAD4 exome AF: 0.0534 AC: 39424 AN: 738558 Hom.: 1888 Cov.: 10 AF XY: 0.0512 AC XY: 20245 AN XY: 395362

African (AFR) AF: 0.0749 AC: 1431 AN: 19116

American (AMR) AF: 0.224 AC: 9763 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 1052 AN: 21476

East Asian (EAS) AF: 0.0238 AC: 860 AN: 36118

South Asian (SAS) AF: 0.0532 AC: 3822 AN: 71900

European-Finnish (FIN) AF: 0.0301 AC: 1588 AN: 52702

Middle Eastern (MID) AF: 0.0380 AC: 165 AN: 4342

European-Non Finnish (NFE) AF: 0.0415 AC: 18778 AN: 452892

Other (OTH) AF: 0.0540 AC: 1965 AN: 36414

GnomAD4 genome AF: 0.0607 AC: 9139 AN: 150600 Hom.: 381 Cov.: 31 AF XY: 0.0601 AC XY: 4410 AN XY: 73416

African (AFR) AF: 0.0714 AC: 2917 AN: 40858

American (AMR) AF: 0.147 AC: 2214 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3464

East Asian (EAS) AF: 0.0208 AC: 107 AN: 5156

South Asian (SAS) AF: 0.0543 AC: 260 AN: 4788

European-Finnish (FIN) AF: 0.0283 AC: 289 AN: 10196

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0445 AC: 3016 AN: 67818

Other (OTH) AF: 0.0667 AC: 138 AN: 2070

Alfa AF: 0.0500 Hom.: 47

Bravo AF: 0.0745

Asia WGS AF: 0.0430 AC: 152 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		0.093
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10485188; hg19: chr6-116951761;