11-6498224-G-A

Position:

• chr11-6498224-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144666.3(DNHD1):​c.9G>A​(p.Pro3Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 1,611,448 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.010 (95 hom.)
• Consequence: DNHD1 NM_144666.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.88

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-6498224-G-A is Benign according to our data. Variant chr11-6498224-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 770398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00607 (925/152304) while in subpopulation NFE AF= 0.00937 (637/68018). AF 95% confidence interval is 0.00876. There are 6 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNHD1	NM_144666.3	c.9G>A	p.Pro3Pro	synonymous_variant	3/43	ENST00000254579.11	NP_653267.2
DNHD1	NM_173589.4	c.9G>A	p.Pro3Pro	synonymous_variant	2/8		NP_775860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNHD1	ENST00000254579.11	c.9G>A	p.Pro3Pro	synonymous_variant	3/43	5	NM_144666.3	ENSP00000254579.6
ENSG00000283977	ENST00000640959.1	n.*252G>A		non_coding_transcript_exon_variant	5/5	4		ENSP00000491841.1
ENSG00000283977	ENST00000640959.1	n.*252G>A		3_prime_UTR_variant	5/5	4		ENSP00000491841.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00936

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00704 AC: 1760 AN: 249974 Hom.: 9 AF XY: 0.00679 AC XY: 917 AN XY: 135084

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00736

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00289

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00817

GnomAD4 exome AF: 0.0101 AC: 14769 AN: 1459144 Hom.: 95 Cov.: 33 AF XY: 0.00985 AC XY: 7147 AN XY: 725444

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00759

Gnomad4 ASJ exome AF: 0.00769

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.00560

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00984

GnomAD4 genome AF: 0.00607 AC: 925 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00529 AC XY: 394 AN XY: 74468

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00937

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00652 Hom.: 4

Bravo AF: 0.00654

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DNHD1: BP4, BP7, BS2 -

DNHD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.31
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs117055865; hg19: chr11-6519454; COSMIC: COSV99600261;