21-42475786-C-T

Variant names:

• chr21-42475786-C-T
• rs78900688
• NM_080860.4:c.877+112G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_080860.4(RSPH1):​c.877+112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,257,322 control chromosomes in the GnomAD database, including 2,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (174 hom., cov: 25)
  • Exomes 𝑓: 0.058 (2105 hom.)
• Consequence: RSPH1 NM_080860.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-42475786-C-T is Benign according to our data. Variant chr21-42475786-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271573.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

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.877+112G>A		intron	N/A	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.763+112G>A		intron	N/A	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.877+112G>A		intron	N/A	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.805+112G>A		intron	N/A	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.763+112G>A		intron	N/A	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 6203 AN: 127564 Hom.: 172 Cov.: 25

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0331

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000665

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0948

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.0560

GnomAD4 exome AF: 0.0578 AC: 65298 AN: 1129634 Hom.: 2105 AF XY: 0.0573 AC XY: 32353 AN XY: 564798

African (AFR) AF: 0.0360 AC: 957 AN: 26584

American (AMR) AF: 0.0330 AC: 1180 AN: 35752

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2038 AN: 19644

East Asian (EAS) AF: 0.000134 AC: 5 AN: 37424

South Asian (SAS) AF: 0.0251 AC: 1655 AN: 66024

European-Finnish (FIN) AF: 0.0561 AC: 2162 AN: 38542

Middle Eastern (MID) AF: 0.0904 AC: 423 AN: 4680

European-Non Finnish (NFE) AF: 0.0634 AC: 54046 AN: 852556

Other (OTH) AF: 0.0585 AC: 2832 AN: 48428

GnomAD4 genome AF: 0.0487 AC: 6218 AN: 127688 Hom.: 174 Cov.: 25 AF XY: 0.0474 AC XY: 2848 AN XY: 60078

African (AFR) AF: 0.0343 AC: 1189 AN: 34684

American (AMR) AF: 0.0375 AC: 409 AN: 10902

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 325 AN: 3212

East Asian (EAS) AF: 0.000666 AC: 3 AN: 4502

South Asian (SAS) AF: 0.0139 AC: 37 AN: 2670

European-Finnish (FIN) AF: 0.0501 AC: 453 AN: 9044

Middle Eastern (MID) AF: 0.0944 AC: 27 AN: 286

European-Non Finnish (NFE) AF: 0.0610 AC: 3672 AN: 60192

Other (OTH) AF: 0.0551 AC: 76 AN: 1380

Alfa AF: 0.0510 Hom.: 32

Bravo AF: 0.0484

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.35
DANN	Benign	0.40
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs78900688; hg19: chr21-43895896;