chr21-42472589-C-T

Position:

• chr21-42472589-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 72 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.*229G>A		3_prime_UTR_variant	9/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.*229G>A		3_prime_UTR_variant	8/8		NP_001273435.1
RSPH1	XM_005261208.3	c.*229G>A		3_prime_UTR_variant	7/7		XP_005261265.1
RSPH1	XM_011529786.2	c.*229G>A		3_prime_UTR_variant	8/8		XP_011528088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.*229G>A		3_prime_UTR_variant	9/9	1	NM_080860.4	ENSP00000291536	P1
RSPH1	ENST00000493019.1	n.2777G>A		non_coding_transcript_exon_variant	8/8	2

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

Gnomad4 AFR exome AF: 0.00819

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0666

Gnomad4 EAS exome AF: 0.0000547

Gnomad4 SAS exome AF: 0.0120

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0389

Gnomad4 OTH exome AF: 0.0370

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

Gnomad4 AFR AF: 0.00690

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.0691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0316

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0386 Hom.: 100

Bravo AF: 0.0258

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.78

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: rs17114994; hg19: chr21-43892699;