6-158999770-G-T

Variant names:

• chr6-158999770-G-T
• rs41267757
• NM_031924.8:c.-220C>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_031924.8(RSPH3):​c.-220C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,610,958 control chromosomes in the GnomAD database, including 414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.022 (381 hom.)
• Consequence: RSPH3 NM_031924.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.33
• Publications: 4 publications found

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

TAGAP-AS1 (HGNC:55239): (TAGAP antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-158999770-G-T is Benign according to our data. Variant chr6-158999770-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475826.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 = 0.0178 (2707/152230) while in subpopulation NFE AF = 0.0237 (1609/67996). AF 95% confidence interval is 0.0227. There are 33 homozygotes in GnomAd4. There are 1288 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.-220C>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.-220C>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_031924.8	ENSP00000356036.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2705 AN: 152112 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00895

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0167 AC: 4153 AN: 248796 AF XY: 0.0171

Gnomad AFR exome AF: 0.00865

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0216 AC: 31553 AN: 1458728 Hom.: 381 Cov.: 32 AF XY: 0.0213 AC XY: 15410 AN XY: 725126

African (AFR) AF: 0.0102 AC: 340 AN: 33452

American (AMR) AF: 0.0152 AC: 677 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00746 AC: 194 AN: 25988

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39626

South Asian (SAS) AF: 0.0128 AC: 1104 AN: 86018

European-Finnish (FIN) AF: 0.0156 AC: 829 AN: 53258

Middle Eastern (MID) AF: 0.0247 AC: 142 AN: 5754

European-Non Finnish (NFE) AF: 0.0244 AC: 27135 AN: 1109860

Other (OTH) AF: 0.0187 AC: 1126 AN: 60226

GnomAD4 genome AF: 0.0178 AC: 2707 AN: 152230 Hom.: 33 Cov.: 32 AF XY: 0.0173 AC XY: 1288 AN XY: 74434

African (AFR) AF: 0.00926 AC: 385 AN: 41556

American (AMR) AF: 0.0233 AC: 357 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00895 AC: 43 AN: 4802

European-Finnish (FIN) AF: 0.0154 AC: 164 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1609 AN: 67996

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.0182 Hom.: 13

Bravo AF: 0.0179

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0240

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 32 Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 13, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.030
DANN	Benign	0.71
PhyloP100		-3.3
PromoterAI		-0.095	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs41267757; hg19: chr6-159420802; COSMIC: COSV51922300; COSMIC: COSV51922300;