rs138940904

Positions:

• chr3-52395006-G-A
• chr3-52395006-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.10915G>A​(p.Ala3639Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,611,868 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.81

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]

DNAH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062885165).
• BP6: Variant 3-52395006-G-A is Benign according to our data. Variant chr3-52395006-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478392.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-52395006-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00127 (193/152298) while in subpopulation AMR AF= 0.00411 (63/15310). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10915G>A	p.Ala3639Thr	missense_variant	68/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10984G>A	p.Ala3662Thr	missense_variant	70/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10915G>A	p.Ala3639Thr	missense_variant	69/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10858G>A	p.Ala3620Thr	missense_variant	69/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10915G>A	p.Ala3639Thr	missense_variant	68/78	1	NM_015512.5	ENSP00000401514.2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00129 AC: 315 AN: 244482 Hom.: 1 AF XY: 0.00133 AC XY: 176 AN XY: 132750

Gnomad AFR exome AF: 0.000538

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000908

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00124 AC: 1812 AN: 1459570 Hom.: 3 Cov.: 32 AF XY: 0.00117 AC XY: 846 AN XY: 725842

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.000997

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.000677

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74466

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000965 AC: 4

ESP6500EA AF: 0.00179 AC: 15

ExAC AF: 0.00138 AC: 167

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.87	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Vest4		0.75
MVP		0.51
MPC		0.56
ClinPred		0.030	T
GERP RS		4.5
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138940904; hg19: chr3-52429022; COSMIC: COSV101326241; COSMIC: COSV101326241;