rs547809161

Variant names:

• chr21-43169019-G-A
• rs547809161
• NM_000394.4:c.-81G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000394.4(CRYAA):​c.-81G>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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (190 hom., cov: 7)
  • Exomes 𝑓: 0.0098 (1127 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.161

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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-43169019-G-A is Benign according to our data. Variant chr21-43169019-G-A is described in ClinVar as [Benign]. Clinvar id is 3911496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.-81G>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+2018C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.-81G>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000482775.1	n.-68G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 627 AN: 68920 Hom.: 190 Cov.: 7

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.0160

Gnomad EAS AF: 0.000234

Gnomad SAS AF: 0.000970

Gnomad FIN AF: 0.00491

Gnomad MID AF: 0.0133

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0213

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00985 AC: 3669 AN: 372564 Hom.: 1127 Cov.: 4 AF XY: 0.00950 AC XY: 1933 AN XY: 203432

African (AFR) AF: 0.00302 AC: 22 AN: 7274

American (AMR) AF: 0.00899 AC: 179 AN: 19910

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 212 AN: 11910

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31586

South Asian (SAS) AF: 0.00116 AC: 59 AN: 50788

European-Finnish (FIN) AF: 0.00521 AC: 122 AN: 23404

Middle Eastern (MID) AF: 0.00795 AC: 15 AN: 1886

European-Non Finnish (NFE) AF: 0.0138 AC: 2842 AN: 206048

Other (OTH) AF: 0.0110 AC: 217 AN: 19758

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00909 AC: 627 AN: 68960 Hom.: 190 Cov.: 7 AF XY: 0.00779 AC XY: 259 AN XY: 33268

African (AFR) AF: 0.00268 AC: 31 AN: 11568

American (AMR) AF: 0.00797 AC: 60 AN: 7532

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 31 AN: 1938

East Asian (EAS) AF: 0.000235 AC: 1 AN: 4254

South Asian (SAS) AF: 0.000971 AC: 3 AN: 3090

European-Finnish (FIN) AF: 0.00491 AC: 23 AN: 4684

Middle Eastern (MID) AF: 0.0154 AC: 2 AN: 130

European-Non Finnish (NFE) AF: 0.0133 AC: 457 AN: 34282

Other (OTH) AF: 0.0208 AC: 19 AN: 914

Alfa AF: 0.00572 Hom.: 20

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.4
DANN	Benign	0.51
PhyloP100		0.16
PromoterAI		-0.029	Neutral
Mutation Taster		=300/0	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

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Other links and lift over

dbSNP: rs547809161; hg19: chr21-44589129;