11-6498712-C-T

Position:

• chr11-6498712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_144666.3(DNHD1):​c.497C>T​(p.Pro166Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNHD1 NM_144666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.32280266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNHD1	NM_144666.3	c.497C>T	p.Pro166Leu	missense_variant	3/43	ENST00000254579.11	NP_653267.2
DNHD1	NM_173589.4	c.497C>T	p.Pro166Leu	missense_variant	2/8		NP_775860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNHD1	ENST00000254579.11	c.497C>T	p.Pro166Leu	missense_variant	3/43	5	NM_144666.3	ENSP00000254579.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 92

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.497C>T (p.P166L) 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 497, causing the proline (P) at amino acid position 166 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	0.21
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0078	T;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;D;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.28
MutPred		0.28		Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);
MVP		0.54
MPC		0.52
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6519942;