chr12-25123217-A-C

Variant names:

• chr12-25123217-A-C
• rs780365545
• NM_018272.5:c.1072T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018272.5(DNAI7):​c.1072T>G​(p.Ser358Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,585,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DNAI7 NM_018272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.232
• Publications: 0 publications found

Genes affected

DNAI7 (HGNC:29599): (dynein axonemal intermediate chain 7) Predicted to enable beta-tubulin binding activity and microtubule binding activity. Predicted to be located in cilium; cytoplasm; and microtubule cytoskeleton. Predicted to be part of axonemal dynein complex. Predicted to be active in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053210407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI7	NM_018272.5	c.1072T>G	p.Ser358Ala	missense_variant	Exon 10 of 16	ENST00000395987.8	NP_060742.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI7	ENST00000395987.8	c.1072T>G	p.Ser358Ala	missense_variant	Exon 10 of 16	1	NM_018272.5	ENSP00000379310.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236794 AF XY: 0.00000780

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433192 Hom.: 0 Cov.: 26 AF XY: 0.00000280 AC XY: 2 AN XY: 714056

African (AFR) AF: 0.00 AC: 0 AN: 32594

American (AMR) AF: 0.0000473 AC: 2 AN: 42328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092976

Other (OTH) AF: 0.0000169 AC: 1 AN: 59344

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1072T>G (p.S358A) alteration is located in exon 10 (coding exon 10) of the CASC1 gene. This alteration results from a T to G substitution at nucleotide position 1072, causing the serine (S) at amino acid position 358 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.2
DANN	Benign	0.27
DEOGEN2	Benign	0.0064	.;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.41	T;T;T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.053	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L;.;.
PhyloP100		-0.23
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.72	T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T
Polyphen		0.0080	B;B;B;.;.
Vest4		0.15
MutPred		0.43		.;Gain of catalytic residue at Q361 (P = 0.0394);.;.;.;
MVP		0.18
MPC		0.048
ClinPred		0.039	T
GERP RS		-1.7
Varity_R		0.033
gMVP		0.15
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs780365545; hg19: chr12-25276151;