11-6498463-A-G

Position:

• chr11-6498463-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144666.3(DNHD1):​c.248A>G​(p.Tyr83Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DNHD1 NM_144666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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]

ENSG00000283977 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNHD1	NM_144666.3	c.248A>G	p.Tyr83Cys	missense_variant	3/43	ENST00000254579.11	NP_653267.2
DNHD1	NM_173589.4	c.248A>G	p.Tyr83Cys	missense_variant	2/8		NP_775860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNHD1	ENST00000254579.11	c.248A>G	p.Tyr83Cys	missense_variant	3/43	5	NM_144666.3	ENSP00000254579.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 91 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

DNHD1: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.70	T;T;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.21
Sift	Benign	0.045	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.59
MutPred		0.53		Gain of catalytic residue at L84 (P = 0.0823);Gain of catalytic residue at L84 (P = 0.0823);Gain of catalytic residue at L84 (P = 0.0823);
MVP		0.48
MPC		0.63
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1279106899; hg19: chr11-6519693;