11-6498319-C-T

Variant names:

• chr11-6498319-C-T
• rs886653281
• NM_144666.3:c.104C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144666.3(DNHD1):​c.104C>T​(p.Pro35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000026 (0 hom., cov: 33)
• Consequence: DNHD1 NM_144666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0990

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05866775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNHD1	NM_144666.3	c.104C>T	p.Pro35Leu	missense_variant	Exon 3 of 43	ENST00000254579.11	NP_653267.2
DNHD1	NM_173589.4	c.104C>T	p.Pro35Leu	missense_variant	Exon 2 of 8		NP_775860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNHD1	ENST00000254579.11	c.104C>T	p.Pro35Leu	missense_variant	Exon 3 of 43	5	NM_144666.3	ENSP00000254579.6
ENSG00000283977	ENST00000640959.1	n.*347C>T		downstream_gene_variant		4		ENSP00000491841.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104C>T (p.P35L) alteration is located in exon 3 (coding exon 1) of the DNHD1 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the proline (P) at amino acid position 35 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.7
DANN	Benign	0.66
DEOGEN2	Benign	0.0056	T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.0030
Sift	Benign	0.044	D;D;D
Sift4G	Uncertain	0.0030	D;T;D
Polyphen		0.028	B;B;B
Vest4		0.14
MutPred		0.21		Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);
MVP		0.21
MPC		0.12
ClinPred		0.071	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.11

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: rs886653281; hg19: chr11-6519549;