NM_144666.3:c.67T>A

Variant names:

• chr11-6498282-T-A
• rs948621562
• NM_144666.3:c.67T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144666.3(DNHD1):​c.67T>A​(p.Trp23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNHD1 NM_144666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.218
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 65

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000283977 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03834954).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144666.3. 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
	DNHD1	NM_144666.3	MANE Select	c.67T>A	p.Trp23Arg	missense	Exon 3 of 43	NP_653267.2	Q96M86-3
	DNHD1	NM_173589.4		c.67T>A	p.Trp23Arg	missense	Exon 2 of 8	NP_775860.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNHD1	ENST00000254579.11	TSL:5 MANE Select	c.67T>A	p.Trp23Arg	missense	Exon 3 of 43	ENSP00000254579.6	Q96M86-3
	DNHD1	ENST00000354685.7	TSL:1	c.67T>A	p.Trp23Arg	missense	Exon 2 of 8	ENSP00000346716.3	Q96M86-4
	DNHD1	ENST00000473019.5	TSL:2	n.156-441T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.22
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.0080
Sift	Benign	0.39	T
Sift4G	Uncertain	0.031	D
Polyphen		0.0	B
Vest4		0.041
MutPred		0.25		Gain of sheet (P = 0.0477)
MVP		0.13
MPC		0.24
ClinPred		0.043	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.063
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs948621562; hg19: chr11-6519512;