NM_000394.4:c.-62G>A

Variant names:

• chr21-43169038-G-A
• rs151103202
• NM_000394.4:c.-62G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000394.4(CRYAA):​c.-62G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0085 (227 hom., cov: 9)
  • Exomes 𝑓: 0.0013 (238 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0290

Genes affected

CRYAA (HGNC:2388): (crystallin alpha A) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]

LOC107987300 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 21-43169038-G-A is Benign according to our data. Variant chr21-43169038-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1703391.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00854 (649/76028) while in subpopulation AFR AF = 0.0446 (598/13404). AF 95% confidence interval is 0.0417. There are 227 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 9. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 227 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.-62G>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+1999C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.-62G>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000482775.1	n.-49G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 645 AN: 75984 Hom.: 226 Cov.: 9

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00435

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: 0.0000536

Gnomad OTH AF: 0.0132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00135 AC: 647 AN: 480432 Hom.: 238 Cov.: 5 AF XY: 0.00109 AC XY: 280 AN XY: 257566

African (AFR) AF: 0.0538 AC: 465 AN: 8650

American (AMR) AF: 0.00241 AC: 69 AN: 28586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14100

East Asian (EAS) AF: 0.00 AC: 0 AN: 34154

South Asian (SAS) AF: 0.000101 AC: 6 AN: 59640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26458

Middle Eastern (MID) AF: 0.000787 AC: 2 AN: 2540

European-Non Finnish (NFE) AF: 0.0000354 AC: 10 AN: 282434

Other (OTH) AF: 0.00398 AC: 95 AN: 23870

GnomAD4 genome AF: 0.00854 AC: 649 AN: 76028 Hom.: 227 Cov.: 9 AF XY: 0.00831 AC XY: 307 AN XY: 36936

African (AFR) AF: 0.0446 AC: 598 AN: 13404

American (AMR) AF: 0.00434 AC: 36 AN: 8302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2098

East Asian (EAS) AF: 0.00 AC: 0 AN: 4468

South Asian (SAS) AF: 0.00 AC: 0 AN: 3340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.0000536 AC: 2 AN: 37318

Other (OTH) AF: 0.0129 AC: 13 AN: 1008

Alfa AF: 0.00204 Hom.: 2

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.87
PhyloP100		0.029
PromoterAI		-0.030	Neutral
Mutation Taster		=296/4	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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs151103202; hg19: chr21-44589148;