rs55931436

Positions:

• chr3-52331207-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.931G>A​(p.Asp311Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,608,908 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.21

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002361536).
• BP6: Variant 3-52331207-G-A is Benign according to our data. Variant chr3-52331207-G-A is described in ClinVar as [Benign]. Clinvar id is 478509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2105/152288) while in subpopulation AFR AF= 0.0479 (1992/41550). AF 95% confidence interval is 0.0462. There are 63 homozygotes in gnomad4. There are 1033 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.931G>A	p.Asp311Asn	missense_variant	7/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.931G>A	p.Asp311Asn	missense_variant	8/80		XP_016861618.1
DNAH1	XM_017006130.2	c.931G>A	p.Asp311Asn	missense_variant	8/79		XP_016861619.1
DNAH1	XM_017006131.2	c.931G>A	p.Asp311Asn	missense_variant	8/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.931G>A	p.Asp311Asn	missense_variant	7/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.1192G>A		non_coding_transcript_exon_variant	7/77	2
DNAH1	ENST00000497875.1	n.1096G>A		non_coding_transcript_exon_variant	8/21	2

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2100 AN: 152170 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00322 AC: 771 AN: 239210 Hom.: 21 AF XY: 0.00238 AC XY: 309 AN XY: 129638

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000739

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00135 AC: 1961 AN: 1456620 Hom.: 44 Cov.: 31 AF XY: 0.00111 AC XY: 804 AN XY: 723874

Gnomad4 AFR exome AF: 0.0490

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000460

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.0138 AC: 2105 AN: 152288 Hom.: 63 Cov.: 32 AF XY: 0.0139 AC XY: 1033 AN XY: 74466

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00262 Hom.: 13

Bravo AF: 0.0154

ESP6500AA AF: 0.0409 AC: 167

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00405 AC: 490

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.071
Sift	Benign	0.089	T
Sift4G	Benign	0.20	T
Vest4		0.29
MVP		0.30
MPC		0.13
ClinPred		0.014	T
GERP RS		3.6
gMVP		0.49

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: rs55931436; hg19: chr3-52365223; COSMIC: COSV99066700;