chr7-21854375-G-T

Variant names:

• chr7-21854375-G-T
• rs4722064
• NM_001277115.2:c.11122G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.11122G>T​(p.Val3708Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,110 control chromosomes in the GnomAD database, including 339,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25986 hom., cov: 31)
  • Exomes 𝑓: 0.65 (313426 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.28
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.795036E-6).
• BP6: Variant 7-21854375-G-T is Benign according to our data. Variant chr7-21854375-G-T is described in ClinVar as Benign. ClinVar VariationId is 163121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

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.11122G>T	p.Val3708Leu	missense	Exon 68 of 82	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.11122G>T	p.Val3708Leu	missense	Exon 68 of 82	ENSP00000475939.1	Q96DT5
	DNAH11	ENST00000421290.1	TSL:4	n.305G>T		non_coding_transcript_exon	Exon 3 of 4
	DNAH11	ENST00000607413.5	TSL:4	n.385G>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86483 AN: 151744 Hom.: 25988 Cov.: 31

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.616

GnomAD2 exomes AF: 0.571 AC: 141939 AN: 248784 AF XY: 0.576

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.671

Gnomad EAS exome AF: 0.325

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.648 AC: 946188 AN: 1461248 Hom.: 313426 Cov.: 47 AF XY: 0.643 AC XY: 467741 AN XY: 726928

African (AFR) AF: 0.406 AC: 13578 AN: 33472

American (AMR) AF: 0.469 AC: 20941 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17389 AN: 26124

East Asian (EAS) AF: 0.343 AC: 13592 AN: 39668

South Asian (SAS) AF: 0.459 AC: 39604 AN: 86200

European-Finnish (FIN) AF: 0.633 AC: 33778 AN: 53364

Middle Eastern (MID) AF: 0.632 AC: 3643 AN: 5768

European-Non Finnish (NFE) AF: 0.689 AC: 766209 AN: 1111608

Other (OTH) AF: 0.621 AC: 37454 AN: 60360

GnomAD4 genome AF: 0.570 AC: 86504 AN: 151862 Hom.: 25986 Cov.: 31 AF XY: 0.559 AC XY: 41488 AN XY: 74200

African (AFR) AF: 0.413 AC: 17104 AN: 41398

American (AMR) AF: 0.532 AC: 8119 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2352 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1705 AN: 5150

South Asian (SAS) AF: 0.444 AC: 2133 AN: 4800

European-Finnish (FIN) AF: 0.638 AC: 6710 AN: 10522

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46304 AN: 67952

Other (OTH) AF: 0.610 AC: 1285 AN: 2108

Alfa AF: 0.637 Hom.: 116998

Bravo AF: 0.556

TwinsUK AF: 0.697 AC: 2586

ALSPAC AF: 0.683 AC: 2634

ESP6500AA AF: 0.421 AC: 1548

ESP6500EA AF: 0.679 AC: 5556

ExAC AF: 0.570 AC: 68826

Asia WGS AF: 0.357 AC: 1244 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	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
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0000088	T
MetaSVM	Benign	-0.98	T
PhyloP100		3.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.068
Sift	Uncertain	0.010	D
Vest4		0.14
MutPred		0.42		Gain of glycosylation at P3714 (P = 0.1154)
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.54
Mutation Taster		=99/1	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: rs4722064; hg19: chr7-21893993; COSMIC: COSV60970603;