rs778123315

Variant names:

• chr21-42477326-G-A
• rs778123315
• NM_080860.4:c.692C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-42477326-G-A
• chr21-42477326-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080860.4(RSPH1):​c.692C>T​(p.Thr231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,601,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T231T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.517
• Publications: 6 publications found

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]

RSPH1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048211724).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080860.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	NM_080860.4	MANE Select	c.692C>T	p.Thr231Met	missense	Exon 7 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.578C>T	p.Thr193Met	missense	Exon 6 of 8	NP_001273435.1	Q8WYR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.692C>T	p.Thr231Met	missense	Exon 7 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.620C>T	p.Thr207Met	missense	Exon 6 of 8	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.578C>T	p.Thr193Met	missense	Exon 6 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.0000673 AC: 10 AN: 148606 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.000492

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251284 AF XY: 0.000118

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000681 AC: 99 AN: 1453096 Hom.: 0 Cov.: 34 AF XY: 0.0000871 AC XY: 63 AN XY: 722976

African (AFR) AF: 0.000120 AC: 4 AN: 33218

American (AMR) AF: 0.000202 AC: 9 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39036

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000298 AC: 33 AN: 1106226

Other (OTH) AF: 0.0000668 AC: 4 AN: 59906

GnomAD4 genome AF: 0.0000673 AC: 10 AN: 148606 Hom.: 0 Cov.: 33 AF XY: 0.0000553 AC XY: 4 AN XY: 72314

African (AFR) AF: 0.000148 AC: 6 AN: 40448

American (AMR) AF: 0.0000670 AC: 1 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4950

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66942

Other (OTH) AF: 0.000492 AC: 1 AN: 2034

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.88
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.52
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.67	P
Vest4		0.21
MVP		0.20
MPC		0.10
ClinPred		0.070	T
GERP RS		-0.96
Varity_R		0.015
gMVP		0.21
Mutation Taster		=96/4	polymorphism

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: rs778123315; hg19: chr21-43897436; COSMIC: COSV52318357;