rs72657374

Variant names:

• chr7-21765597-G-A
• rs72657374
• NM_001277115.2:c.9102+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-21765597-G-A
• chr7-21765597-G-T
• chr7-21765597-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.9102+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,548,870 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (18 hom., cov: 31)
  • Exomes 𝑓: 0.016 (260 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001321
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.150
• Publications: 2 publications found

Genes affected

DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

DNAH11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-21765597-G-A is Benign according to our data. Variant chr7-21765597-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178729.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2119/144746) while in subpopulation NFE AF = 0.0186 (1232/66088). AF 95% confidence interval is 0.0178. There are 18 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. 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
	DNAH11	NM_001277115.2	MANE Select	c.9102+8G>A		splice_region intron	N/A	NP_001264044.1	Q96DT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.9102+8G>A		splice_region intron	N/A	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2119 AN: 144622 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0113

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00432

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0174

GnomAD2 exomes AF: 0.0121 AC: 2495 AN: 205850 AF XY: 0.0123

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00970

Gnomad EAS exome AF: 0.000126

Gnomad FIN exome AF: 0.00932

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0164 AC: 23045 AN: 1404124 Hom.: 260 Cov.: 32 AF XY: 0.0160 AC XY: 11141 AN XY: 695524

African (AFR) AF: 0.0100 AC: 327 AN: 32538

American (AMR) AF: 0.0119 AC: 480 AN: 40426

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 250 AN: 23724

East Asian (EAS) AF: 0.0000799 AC: 3 AN: 37536

South Asian (SAS) AF: 0.00593 AC: 482 AN: 81246

European-Finnish (FIN) AF: 0.00837 AC: 387 AN: 46250

Middle Eastern (MID) AF: 0.0252 AC: 127 AN: 5034

European-Non Finnish (NFE) AF: 0.0185 AC: 19965 AN: 1079670

Other (OTH) AF: 0.0177 AC: 1024 AN: 57700

GnomAD4 genome AF: 0.0146 AC: 2119 AN: 144746 Hom.: 18 Cov.: 31 AF XY: 0.0135 AC XY: 951 AN XY: 70242

African (AFR) AF: 0.0125 AC: 491 AN: 39380

American (AMR) AF: 0.0162 AC: 223 AN: 13784

Ashkenazi Jewish (ASJ) AF: 0.00789 AC: 27 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4924

South Asian (SAS) AF: 0.00432 AC: 19 AN: 4396

European-Finnish (FIN) AF: 0.00801 AC: 77 AN: 9610

Middle Eastern (MID) AF: 0.0211 AC: 6 AN: 284

European-Non Finnish (NFE) AF: 0.0186 AC: 1232 AN: 66088

Other (OTH) AF: 0.0172 AC: 34 AN: 1974

Alfa AF: 0.0109 Hom.: 6

Bravo AF: 0.0149

Asia WGS AF: 0.00202 AC: 8 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
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: rs72657374; hg19: chr7-21805215; COSMIC: COSV60964567;