21-42475905-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_080860.4(RSPH1):c.870G>A(p.Met290Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,611,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 28)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.80

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

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035790205).
• BP6: Variant 21-42475905-C-T is Benign according to our data. Variant chr21-42475905-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (182/149232) while in subpopulation AFR AF= 0.00435 (177/40654). AF 95% confidence interval is 0.00383. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.870G>A	p.Met290Ile	missense_variant	8/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.756G>A	p.Met252Ile	missense_variant	7/8
RSPH1	XM_011529786.2	c.798G>A	p.Met266Ile	missense_variant	7/8
RSPH1	XM_005261208.3	c.663G>A	p.Met221Ile	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.870G>A	p.Met290Ile	missense_variant	8/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.756G>A	p.Met252Ile	missense_variant	7/8	5
RSPH1	ENST00000493019.1	n.2488G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 182 AN: 149114 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

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: 0.00

Gnomad OTH AF: 0.00100

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251410 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135884

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727228

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000157

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: 0.00000360

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00122 AC: 182 AN: 149232 Hom.: 1 Cov.: 28 AF XY: 0.00117 AC XY: 85 AN XY: 72608

Gnomad4 AFR AF: 0.00435

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000991

Alfa AF: 0.000208 Hom.: 0

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000453 AC: 55

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

RSPH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.038
Dann	Benign	0.31
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.19		Loss of phosphorylation at Y288 (P = 0.131);.;
MVP		0.040
MPC		0.11
ClinPred		0.0052	T
GERP RS		-5.7
Varity_R		0.041
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140450252; hg19: chr21-43896015; COSMIC: COSV99370519;