chr21-42472589-C-T

Variant names:

• chr21-42472589-C-T
• rs17114994
• NM_080860.4:c.*229G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080860.4(RSPH1):​c.*229G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 389,198 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (72 hom., cov: 33)
  • Exomes 𝑓: 0.034 (150 hom.)
• Consequence: RSPH1 NM_080860.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.470
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-42472589-C-T is Benign according to our data. Variant chr21-42472589-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1203261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0268 (4086/152312) while in subpopulation NFE AF = 0.0388 (2636/68022). AF 95% confidence interval is 0.0375. There are 72 homozygotes in GnomAd4. There are 1957 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AR,AD gene

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.*229G>A		3_prime_UTR	Exon 9 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.*229G>A		3_prime_UTR	Exon 8 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.*229G>A		3_prime_UTR	Exon 9 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.*229G>A		3_prime_UTR	Exon 8 of 8	ENSP00000526578.1
	RSPH1	ENST00000856518.1		c.*229G>A		3_prime_UTR	Exon 7 of 7	ENSP00000526577.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4088 AN: 152194 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0339 AC: 8030 AN: 236886 Hom.: 150 Cov.: 0 AF XY: 0.0334 AC XY: 4092 AN XY: 122600

African (AFR) AF: 0.00819 AC: 53 AN: 6472

American (AMR) AF: 0.0249 AC: 178 AN: 7140

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 561 AN: 8422

East Asian (EAS) AF: 0.0000547 AC: 1 AN: 18294

South Asian (SAS) AF: 0.0120 AC: 152 AN: 12620

European-Finnish (FIN) AF: 0.0359 AC: 605 AN: 16868

Middle Eastern (MID) AF: 0.0513 AC: 61 AN: 1190

European-Non Finnish (NFE) AF: 0.0389 AC: 5865 AN: 150894

Other (OTH) AF: 0.0370 AC: 554 AN: 14986

GnomAD4 genome AF: 0.0268 AC: 4086 AN: 152312 Hom.: 72 Cov.: 33 AF XY: 0.0263 AC XY: 1957 AN XY: 74474

African (AFR) AF: 0.00690 AC: 287 AN: 41576

American (AMR) AF: 0.0271 AC: 414 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4826

European-Finnish (FIN) AF: 0.0316 AC: 335 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2636 AN: 68022

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0370 Hom.: 118

Bravo AF: 0.0258

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.78
PhyloP100		0.47
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: rs17114994; hg19: chr21-43892699;