chr21-42477291-T-G

Variant names:

• chr21-42477291-T-G
• rs137935071
• NM_080860.4:c.727A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080860.4(RSPH1):​c.727A>C​(p.Ser243Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S243G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense, splice_region
• Scores: Splicing: ADA: 0.001327
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061087668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.727A>C	p.Ser243Arg	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.613A>C	p.Ser205Arg	missense_variant, splice_region_variant	Exon 6 of 8		NP_001273435.1
RSPH1	XM_011529786.2	c.655A>C	p.Ser219Arg	missense_variant, splice_region_variant	Exon 6 of 8		XP_011528088.1
RSPH1	XM_005261208.3	c.520A>C	p.Ser174Arg	missense_variant, splice_region_variant	Exon 5 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.727A>C	p.Ser243Arg	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.613A>C	p.Ser205Arg	missense_variant, splice_region_variant	Exon 6 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2345A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338668 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 665500

African (AFR) AF: 0.0000330 AC: 1 AN: 30260

American (AMR) AF: 0.00 AC: 0 AN: 42086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22602

East Asian (EAS) AF: 0.00 AC: 0 AN: 27656

South Asian (SAS) AF: 0.00 AC: 0 AN: 83574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032212

Other (OTH) AF: 0.00 AC: 0 AN: 52756

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.39
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.044
Sift	Benign	0.054	T;D
Sift4G	Benign	0.47	T;T
Polyphen		0.072	B;.
Vest4		0.13
MutPred		0.27		Loss of phosphorylation at S243 (P = 0.0089);.;
MVP		0.088
MPC		0.14
ClinPred		0.45	T
GERP RS		0.88
Varity_R		0.068
gMVP		0.18
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs137935071; hg19: chr21-43897401;