11-6498412-G-A

Position:

• chr11-6498412-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_144666.3(DNHD1):​c.197G>A​(p.Arg66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,613,920 control chromosomes in the GnomAD database, including 196,700 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.45 (15822 hom., cov: 32)
  • Exomes 𝑓: 0.49 (180878 hom.)
• Consequence: DNHD1 NM_144666.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.815

Genes affected

DNHD1 (HGNC:26532): (dynein heavy chain domain 1) Predicted to enable dynein intermediate chain binding activity; dynein light intermediate chain binding activity; and minus-end-directed microtubule motor activity. Predicted to be involved in cilium movement. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

DNHD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNHD1. . Gene score misZ 3.4791 (greater than the threshold 3.09). Trascript score misZ 3.2933 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 65.
• BP4: Computational evidence support a benign effect (MetaRNN=6.287139E-5).
• BP6: Variant 11-6498412-G-A is Benign according to our data. Variant chr11-6498412-G-A is described in ClinVar as [Benign]. Clinvar id is 3059428.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNHD1	NM_144666.3	c.197G>A	p.Arg66Gln	missense_variant	3/43	ENST00000254579.11	NP_653267.2
DNHD1	NM_173589.4	c.197G>A	p.Arg66Gln	missense_variant	2/8		NP_775860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNHD1	ENST00000254579.11	c.197G>A	p.Arg66Gln	missense_variant	3/43	5	NM_144666.3	ENSP00000254579.6

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67676 AN: 151932 Hom.: 15812 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.450

GnomAD3 exomes AF: 0.459 AC: 115392 AN: 251168 Hom.: 27925 AF XY: 0.461 AC XY: 62624 AN XY: 135772

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.493 AC: 719979 AN: 1461868 Hom.: 180878 Cov.: 86 AF XY: 0.492 AC XY: 358019 AN XY: 727240

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.508

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.446

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.445 AC: 67715 AN: 152052 Hom.: 15822 Cov.: 32 AF XY: 0.438 AC XY: 32539 AN XY: 74324

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.447

Alfa AF: 0.496 Hom.: 29898

Bravo AF: 0.443

TwinsUK AF: 0.522 AC: 1937

ALSPAC AF: 0.509 AC: 1960

ESP6500AA AF: 0.348 AC: 1531

ESP6500EA AF: 0.524 AC: 4499

ExAC AF: 0.461 AC: 55978

Asia WGS AF: 0.307 AC: 1071 AN: 3478

EpiCase AF: 0.517

EpiControl AF: 0.518

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DNHD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.76
DANN	Benign	0.77
DEOGEN2	Benign	0.0076	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.61	T;T;.
MetaRNN	Benign	0.000063	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.46	N;N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.057
MPC		0.14
ClinPred		0.0031	T
GERP RS		0.16
Varity_R		0.028
gMVP		0.046

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: rs11604149; hg19: chr11-6519642; COSMIC: COSV54435936; COSMIC: COSV54435936;