chr21-42475749-C-T

Variant names:

• chr21-42475749-C-T
• rs73374124
• NM_080860.4:c.877+149G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_080860.4(RSPH1):​c.877+149G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 639,842 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 24)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: RSPH1 NM_080860.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.714
• Publications: 0 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=-0.89).
• BP6: Variant 21-42475749-C-T is Benign according to our data. Variant chr21-42475749-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1203615.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1497/121942) while in subpopulation AFR AF = 0.042 (1398/33260). AF 95% confidence interval is 0.0402. There are 37 homozygotes in GnomAd4. There are 682 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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.877+149G>A		intron	N/A	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.763+149G>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+149G>A		intron	N/A	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.805+149G>A		intron	N/A	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.763+149G>A		intron	N/A	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1488 AN: 121820 Hom.: 37 Cov.: 24

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00697

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000398

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.00159 AC: 821 AN: 517900 Hom.: 7 AF XY: 0.00129 AC XY: 347 AN XY: 268230

African (AFR) AF: 0.0425 AC: 589 AN: 13874

American (AMR) AF: 0.00419 AC: 76 AN: 18156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30636

South Asian (SAS) AF: 0.00 AC: 0 AN: 33978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24696

Middle Eastern (MID) AF: 0.00320 AC: 7 AN: 2190

European-Non Finnish (NFE) AF: 0.000152 AC: 54 AN: 355566

Other (OTH) AF: 0.00359 AC: 95 AN: 26470

GnomAD4 genome AF: 0.0123 AC: 1497 AN: 121942 Hom.: 37 Cov.: 24 AF XY: 0.0120 AC XY: 682 AN XY: 56832

African (AFR) AF: 0.0420 AC: 1398 AN: 33260

American (AMR) AF: 0.00696 AC: 70 AN: 10062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3116

East Asian (EAS) AF: 0.00 AC: 0 AN: 4368

South Asian (SAS) AF: 0.000399 AC: 1 AN: 2508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8878

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000244 AC: 14 AN: 57442

Other (OTH) AF: 0.0105 AC: 13 AN: 1242

Alfa AF: 0.00744 Hom.: 4

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.89
CADD	Benign	0.29
DANN	Benign	0.59
PhyloP100		-0.71
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: rs73374124; hg19: chr21-43895859;