rs188903141

Positions:

• chr6-116629638-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The ENST00000229554.10(RSPH4A):​c.1734C>T​(p.Asp578=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,612,974 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: RSPH4A ENST00000229554.10 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.471

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]

LOC124901386 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-116629638-C-T is Benign according to our data. Variant chr6-116629638-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.471 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1734C>T	p.Asp578=	synonymous_variant	4/6	ENST00000229554.10	NP_001010892.1
LOC124901386	XR_007059721.1	n.812G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1734C>T	p.Asp578=	synonymous_variant	4/6	1	NM_001010892.3	ENSP00000229554	P1
RSPH4A	ENST00000368581.8	c.1663-797C>T		intron_variant		1		ENSP00000357570
RSPH4A	ENST00000368580.4	c.993C>T	p.Asp331=	synonymous_variant	3/5	5		ENSP00000357569

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 248824 Hom.: 0 AF XY: 0.000245 AC XY: 33 AN XY: 134700

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1460712 Hom.: 2 Cov.: 31 AF XY: 0.000248 AC XY: 180 AN XY: 726758

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74442

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000314

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 10, 2015

p.Asp578Asp in exon 4 of RSPH4A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 16/66676 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs188903141). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.4
DANN	Benign	0.67

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: rs188903141; hg19: chr6-116950801;