3-52331164-G-C

Position:

• chr3-52331164-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015512.5(DNAH1):​c.888G>C​(p.Gln296His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,597,516 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q296R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.05

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005332947).
• BP6: Variant 3-52331164-G-C is Benign according to our data. Variant chr3-52331164-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 478507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.888G>C	p.Gln296His	missense_variant	7/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.888G>C	p.Gln296His	missense_variant	8/80
DNAH1	XM_017006130.2	c.888G>C	p.Gln296His	missense_variant	8/79
DNAH1	XM_017006131.2	c.888G>C	p.Gln296His	missense_variant	8/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.888G>C	p.Gln296His	missense_variant	7/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.1149G>C		non_coding_transcript_exon_variant	7/77	2
DNAH1	ENST00000497875.1	n.1053G>C		non_coding_transcript_exon_variant	8/21	2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000672 AC: 149 AN: 221566 Hom.: 2 AF XY: 0.000844 AC XY: 101 AN XY: 119708

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000286

Gnomad ASJ exome AF: 0.00242

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.0000512

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000390 AC: 563 AN: 1445142 Hom.: 3 Cov.: 31 AF XY: 0.000446 AC XY: 320 AN XY: 717046

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000262

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.0000573

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000719

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74524

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000526 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.000253 AC: 1

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000646 AC: 78

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

DNAH1: BP4, BS2 -

DNAH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely 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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.3
DANN	Benign	0.89
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.035
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Vest4		0.096
MutPred		0.26		Loss of methylation at K301 (P = 0.0977);
MVP		0.072
MPC		0.12
ClinPred		0.0011	T
GERP RS		1.8
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200450328; hg19: chr3-52365180;