17-3498977-C-T

Variant names:

• chr17-3498977-C-T
• rs78677072
• NM_000049.4:c.831C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000049.4(ASPA):​c.831C>T​(p.Thr277Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,090 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T277T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: ASPA NM_000049.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.20
• Publications: 4 publications found

Genes affected

ASPA (HGNC:756): (aspartoacylase) This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

SPATA22 (HGNC:30705): (spermatogenesis associated 22) Predicted to be involved in regulation of meiotic cell cycle. Predicted to act upstream of or within several processes, including fertilization; gamete generation; and meiosis I cell cycle process. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

SPATA22 Gene-Disease associations (from GenCC):

• genetic infertility

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-3498977-C-T is Benign according to our data. Variant chr17-3498977-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00382 (581/152264) while in subpopulation AMR AF = 0.0325 (497/15302). AF 95% confidence interval is 0.0301. There are 16 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	NM_000049.4	MANE Select	c.831C>T	p.Thr277Thr	synonymous	Exon 6 of 6	NP_000040.1	Q6FH48
	ASPA	NM_001128085.1		c.831C>T	p.Thr277Thr	synonymous	Exon 7 of 7	NP_001121557.1	P45381
	SPATA22	NM_001321337.2		c.-74+14435G>A		intron	N/A	NP_001308266.1	A0A140VJV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	ENST00000263080.3	TSL:1 MANE Select	c.831C>T	p.Thr277Thr	synonymous	Exon 6 of 6	ENSP00000263080.2	P45381
	ASPA	ENST00000456349.6	TSL:1	c.831C>T	p.Thr277Thr	synonymous	Exon 7 of 7	ENSP00000409976.2	P45381
	ASPA	ENST00000858436.1		c.831C>T	p.Thr277Thr	synonymous	Exon 7 of 7	ENSP00000528495.1

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152146 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00632 AC: 1589 AN: 251312 AF XY: 0.00507

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00150 AC: 2199 AN: 1461826 Hom.: 43 Cov.: 30 AF XY: 0.00136 AC XY: 986 AN XY: 727208

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.0393 AC: 1759 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00693 AC: 275 AN: 39696

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111970

Other (OTH) AF: 0.00149 AC: 90 AN: 60394

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152264 Hom.: 16 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74454

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.0325 AC: 497 AN: 15302

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

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00127 Hom.: 5

Bravo AF: 0.00571

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Spongy degeneration of central nervous system (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.044
DANN	Benign	0.87
PhyloP100		-2.2
Mutation Taster		=99/1	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: rs78677072; hg19: chr17-3402271; COSMIC: COSV53980471;