chr3-52395006-G-T

Position:

• chr3-52395006-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015512.5(DNAH1):​c.10915G>T​(p.Ala3639Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3639T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10915G>T	p.Ala3639Ser	missense_variant	68/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10984G>T	p.Ala3662Ser	missense_variant	70/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10915G>T	p.Ala3639Ser	missense_variant	69/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10858G>T	p.Ala3620Ser	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>T	p.Ala3639Ser	missense_variant	68/78	1	NM_015512.5	ENSP00000401514.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244482 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459572 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Benign	0.070	T
Vest4		0.56
MutPred		0.74		Loss of ubiquitination at K3635 (P = 0.1151);
MVP		0.52
MPC		0.50
ClinPred		0.93	D
GERP RS		4.5
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;