rs151158140

chr21-42476042-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_080860.4(RSPH1):c.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,613,710 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0058 (31 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.462

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005465418).
• BP6: Variant 21-42476042-C-T is Benign according to our data. Variant chr21-42476042-C-T is described in ClinVar as [Benign]. Clinvar id is 241791.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42476042-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00449 (683/151968) while in subpopulation AMR AF= 0.0113 (173/15272). AF 95% confidence interval is 0.00995. There are 1 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.733G>A	p.Gly245Arg	missense_variant	8/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.619G>A	p.Gly207Arg	missense_variant	7/8
RSPH1	XM_011529786.2	c.661G>A	p.Gly221Arg	missense_variant	7/8
RSPH1	XM_005261208.3	c.526G>A	p.Gly176Arg	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.733G>A	p.Gly245Arg	missense_variant	8/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.619G>A	p.Gly207Arg	missense_variant	7/8	5
RSPH1	ENST00000493019.1	n.2351G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 683 AN: 151850 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00433

GnomAD3 exomes AF: 0.00385 AC: 967 AN: 251258 Hom.: 5 AF XY: 0.00378 AC XY: 513 AN XY: 135802

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00530

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00583 AC: 8524 AN: 1461742 Hom.: 31 Cov.: 32 AF XY: 0.00567 AC XY: 4122 AN XY: 727172

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00492

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00449 AC: 683 AN: 151968 Hom.: 1 Cov.: 30 AF XY: 0.00409 AC XY: 304 AN XY: 74268

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00208

Gnomad4 NFE AF: 0.00586

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.00539 Hom.: 2

Bravo AF: 0.00487

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00343 AC: 416

EpiCase AF: 0.00469

EpiControl AF: 0.00587

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.070	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.92	P;.
Vest4		0.33
MutPred		0.32		Gain of loop (P = 0.0045);.;
MVP		0.34
MPC		0.32
ClinPred		0.015	T
GERP RS		1.5
Varity_R		0.082
gMVP		0.30

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: rs151158140; hg19: chr21-43896152; COSMIC: COSV99370790;